JP2008543816A - Novel compounds and their effects on eating behavior - Google Patents

Abstract

Compounds of the invention are novel peptide analogues of oxyntomodulin (oxm) in which one or more amino acids of the oxm sequence have been changed. Changing amino acids 15-24 of oxm to either amino acids 968 - 977 of the ±-latrotoxin peptide (and variations thereof) or amino acids 15 - 24 of exendin-4 (and variations thereof), or combinations of sequences from these sources, and/or changing amino acids 27-33 of oxm to amino acids 27-33 of exendin-4, and/or the addition of amino acids to the C-terminus of the peptide, results in a series of analogues of oxm that demonstrate the oxm like activity of reducing food intake, and with certain embodiments a greater ability to decrease food intake.

Description

  The present invention relates to the use of drugs to control appetite, eating, food intake, energy consumption and caloric intake, treat overweight and obesity, and prevent or treat obesity complications.

According to the World Health Organization (WHO), obesity is a representative example of a globally prevalent disease, with over 1 billion adults fattened, of which at least 300 million are clinically obese The WHO also has 250,000 deaths annually in Europe, with 2 more worldwide.
It is estimated that over 500,000 deaths are attributed to weight (World Health Organization, Global Strategy on Diet, Physical Activity and Health, 2004).

  The causes of obesity are complex and diverse. Various validation results suggest that obesity is not a simple self-control problem, but a complex disorder involving appetite control and energy metabolism. Obesity is also associated with a variety of symptoms associated with an increase in the diseased or dead population. The etiology of obesity is unclear, but genetic, metabolic, biochemical, cultural and psychosocial factors may contribute. In general, obesity is a condition in which excess body fat is harmful to an individual's health.

There is solid evidence that obesity is associated with increased morbidity and mortality. Disease risk, such as cardiovascular disease risk and type 2 diabetes risk, increases independently of an increase in body mass index (BMI). In fact, when these risks are expressed as values, the risk of heart disease in women is increased by 5% and the risk of heart disease in men is increased by 7% when the BMI value exceeds 24.9 respectively (Kenchaiah Et al., N. Engl. J. Med. 347: 305, 2002; Massie, N. Engl. J. Med. 347: 358, 2002). There is also substantial evidence that obesity or overweight people lose weight to reduce important risk factors associated with the disease. In both obese and obese adults, a 10% loss from initial weight reduces risk factors such as hypertension, hyperlipidemia and hyperglycemia.

Saving food and exercise are a simple way to reduce weight gain and promote weight loss, but for those who are overweight or obese, usually control these factors well enough to save weight efficiently. I can't. Therefore, drug therapy is effective. Several weight loss drugs are approved by the US Food and Drug Administration and are available as part of a comprehensive weight loss program. However, many of these drugs have serious side effects. An example of a widely used appetite suppressant is sibutramine (McNeely, W et al., Drugs, 1998, 56 (6), 1093-1124). The primary and secondary metabolites of sibutramine are pharmacologically active, and these products are thought to suppress serotonin and noradrenaline reuptake, increase satiety and increase heat production. . If less invasive methods fail and if the patient is obese at high risk of morbidity or mortality, carefully select patients with clinically severe obesity and perform weight loss surgery Can be arbitrarily selected. However, these treatments are high risk and are appropriate only for a limited number of patients (Wolfe and Morton, JAMA, 2005, 294, 1960-1963). It is not just obese patients who want to lose weight. A person with a weight in the recommended range, for example, the person on the upper limit side of the recommended range, would like to reduce the weight to approach the ideal weight.

Oxint modulin (hereinafter referred to as oxm) is a glucagon superfamily peptide consisting of 37 amino acids having a total glucagon 29 amino acid sequence and an 8 amino acid extension on the carboxy terminus, and is used in the brain and digestive tract. Resulting in tissue-specific processing of pre-pro-glucagon precursors (Holst, Ann Rev Physiol, 1997, 59: 257-271). Administration of oxm to rats by intracerebroventricular injection and injection into the hypothalamic paraventricular nucleus and arcuate nucleus suppresses fasting after fasting (Dakin et al., Endocrinology, 2001, 142: 4244-4250; Dakin et al. , Endocrinology, 2004, 145: 2687-2695). Chronic central administration suppresses weight gain as food intake decreases. (Dakin et al., Am J Physiol Endocrinol Metab, 2002, 283: E1173-E1177). Even peripheral administration twice a day suppresses weight gain and reduces obesity (Dakin et al., Endocrinology, 2004, 145: 2687-2695).

In WO 03/022304, native oxm and its analogues are used as drugs, especially in the field of obesity, to control appetite, food intake, food intake, energy expenditure and caloric intake. It is disclosed. Human studies have shown that intravenous injection of oxm effectively reduces appetite (Cohen et al., J. Clin. Endocrinol Metab, 2003, 88 (10): 4696-4701). In a study to examine the weight loss effect of oxm on humans,
Subcutaneous injection of mg (approximately 400 nmol) three times a day (30 minutes before meals) for 28 days was found to clearly reduce body weight (Wynne et al., Diabetes, 2005, 54: 2390-2395).

  Although native peptides or their analogs are often used for therapy, clearance rates are often high and they are easily degraded, but peptides are nevertheless widely used in the medical industry. In particular, when it is desired to maintain a high blood concentration over a long period of time, it is inconvenient for the therapeutic agent to have high clearance or rapid degradation. This results in the need for repeated doses, worsening patient compliance and increasing treatment costs.

  The receptor for α-latrotoxin, a presynaptic neurotoxin isolated from the venom of the black widow spider (Latrodictus tredecimmuttus), is highly homologous to the major amino acid sequences of the GTP-binding protein-coupled receptor family, including receptors of the glucagon superfamily. It is known to show. The glucagon superfamily includes glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM). ), PACAP, secretin and vasoactive intestinal polypeptide (VIP). Comparison between the main amino acid sequence of α-latrotoxin and the main amino acid sequence of exendin-4 (hereinafter referred to as exendin), a 39 amino acid peptide isolated from the salivary gland of the American lizard (Heloderma suspectum) Reveals the existence of a conserved sequence, which is also conserved in the glucagon superfamily of hormones (glucagon, GLP-1, VIP, oxm) and neuropeptide (PACAP). This fact suggests that these sequences may provide useful therapeutic properties (Holz and Habener, Comp Biochem Physiol, 1998, Part B 121: 177-184).

  There is a need for agents that can be used for efficient weight loss and / or to treat patients with other symptoms of overload, such as diabetes and eating disorders, that can be used in patients who are overweight or obese. In particular, it is structurally similar to oxm, which exhibits better efficacy and / or has a more sustained action profile or treatment-effective action profile and / or exhibits a slower clearance rate compared to native oxm Drugs are needed.

The compounds of the present invention are novel peptides that are oxm analogs (hereinafter referred to as “oxm analogs”), wherein one or more amino acids of the oxm sequence or a part of the oxm sequence is one or more specific substitutions It is replaced with an amino acid or a substituted sequence. Surprisingly, the inventors substituted amino acids 15-24 of oxm with either 968-977 of α-latrotoxin peptide (and variants thereof) or 15-24 of exendin 4 (and variants thereof). Or combine the sequences of the regions and / or replace amino acids 27-33 of oxm with 27-33 of exendin 4 (and variants thereof) and / or add amino acids to the C-terminus of the peptide As a result, it was found that a series of oxm analogs having an oxm-like food intake inhibitory action was obtained, and in some examples, a better food intake inhibitory effect was observed. The region of the peptide hormone has not previously been associated with such properties. Substitution of said region of oxm is thought to result in a beneficial change in the stringency of the α-helical secondary structure of the peptide, thereby enhancing the stability of the analog and / or improving its biological function. The full-length sequence of α-latrotoxin is registered as 1616226A in GenBank. However, it should be noted that the aforementioned numbered residues correspond to the numbered residues of Holz and Habener (ibid), not the numbering in the GenBank registry.

  Surprisingly, by changing the N-terminal sequence of oxm to D-His Ala Asp or D-His Ala Glu in particular, the sequence becomes closer to the GLP-1 sequence, and as a result, it tends to be decomposed into DPPIV. However, it has been found that the appetite suppressing effect of oxm is enhanced.

  The medicinal effects obtained by other amino acid changes in the region are also described along with similar sequences derived to other chemical components such as acyl chains, albumin and PEG species.

  (1) The dose required to reduce food intake to the same extent (or more prominently) is very small (2) The appetite suppressive effect of analogs with enhanced resistance to degradation activity From the typical data, it can be inferred that an increased appetite suppressive effect means an increased potency because is apparently more persistent than native oxm.

The present invention relates to general formula (I):
Z-X-S1 (I)
Represented by
X is oxm 4-14 (according to the nomenclature used herein, means including residues 4-14 of the oxm sequence);
Z is an amino acid sequence having 3 amino acid residues;
S1 is the amino acid sequence corresponding to row A, or the m amino acids of row A are replaced with the corresponding m amino acids of residues 15 to 37 of row B, and t Amino acid sequence corresponding to row A in which the number of amino acid residues is replaced by the corresponding t amino acid residues of residues 15-24 of row R, where row A (SEQ ID NO: 1), row B ( SEQ ID NO: 2) and row R (SEQ ID NO: 145) are as follows:

The compound optionally further has an extension linked to an amino acid at position 37, the optional extension comprising one or more amino acids,
m is an integer of 1 or more,
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (where Z is not His Ser Gln when S1 matches row A), variants thereof Or a derivative, or a salt or solvate thereof.

As a first preferred embodiment, the present invention is a compound of the general formula (II):
Z-X-S2-Y (II)
Represented by
X and Z are as defined in formula (I) above;
Y is oxm 25-37;
S2 is the amino acid sequence corresponding to row C (SEQ ID NO: 3), where n amino acids in row C are replaced with n corresponding amino acids from row D (SEQ ID NO: 4) And the u amino acids in row C are replaced with u corresponding amino acids from row S (SEQ ID NO: 145), where row C, row D and row S are as follows: Yes,

n is an integer of 1 or more,
u provides a compound that is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, a variant or derivative thereof, or a salt or solvate thereof.

As a second preferred embodiment, the present invention provides a compound represented by the general formula (III):
ZX'-S3-Y '(III)
Represented by
X ′ is oxm 4 to 26;
Z is as defined in formula (I) above;
Y ′ is oxm 34-37;
S3 is an amino acid sequence corresponding to row E, wherein the p amino acids in row E are replaced with p corresponding amino acids from row F, and row E (SEQ ID NO: 5) and Row F (SEQ ID NO: 6) is as follows:

  p provides a compound that is an integer of 1 or more, a variant or derivative thereof, or a salt or solvate thereof.

According to a third preferred embodiment, the present invention relates to the above formula (I),
X is as defined in Formula (I) above,
S1 corresponds to at least one sequence of row A as defined in formula (I) above and has at least 6 amino acids;
Z is A ¹ -A ² -A ^3- ;
A ¹ is an amino acid other than L-histidine;
A ² is L-alanine or L-serine;
Provided is a compound wherein A ³ is L-aspartate or L-glutamate or L-glutamine.

The invention also relates to the general formula (VI):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Y Asn Asn Ile Ala-X (VI, SEQ ID
NO: 7)
Represented by
Y is Arg or Lys;
X provides a compound that is at least one amino acid, a variant or derivative thereof, or a salt or solvate thereof.

  Following the principles outlined above, there are more than 160 groups of oxm analogs, most of which reduce food intake more strongly than native oxm.

In order to facilitate review of the various embodiments herein, special terms are described below.
Terminology Animal: A living multi-cellular vertebrate, and the classification includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human subjects and veterinary subjects.

  Appetite: A natural desire or desire for food. In one embodiment, the appetite for food is evaluated to determine appetite. As appetite increases, eating behavior usually increases.

Appetite suppressant: A compound that reduces the desire for food. Commercial appetite suppressants include, but are not limited to, ampepramon (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramine, sibutramine, rimonabant and fluoxetine.

Body mass index (BMI): A mathematical formula for measuring body mass, sometimes referred to as the Ketley index. BMI is calculated by dividing body weight (kg) by height ² (m ² ). The recommended categories of human BMI values that are adopted by Expert Panel on the Identification, Evaluation and Treatment of Overweight and Obesity in Accounts and approved by major institutions engaged by health professionals, etc. are as follows: 18.5 kg / m ² ; standard weight 1
8.5-24.9 kg / m ² ; Overweight 25-29.9 kg / m ² ; Obesity (Class 1) 30-34.9 kg / m ² ; Obesity (Class 2) 35-39.9 kg / m ² ; Extremely obese (class 3) ≧ 40 kg / m ² (Identificaion, Evaluation, and Tr
education of Overweight and Obesity in Adults, The North American Association for the Study of the Obesity (NAASO) and the National Heart, Lung, and B In one embodiment, it can be determined that a patient needs to be treated for overweight or obesity with a BMI value greater than 25 kg / m ² . Ideal weight will vary from species and individual based on height, physique, bone structure and gender.

  Conservative substitution: Replacing an amino acid residue with another conservative residue in a polypeptide. Typical conservative substitutions include intersubstitution between the aliphatic amino acids Ala, Val, Leu and Ile, exchange of Ser and Thr containing hydroxy groups, exchange of Asp and Glu acidic residues, amide-containing residues Exchange of certain Asn and Gln, exchange of basic residues Lys and Arg, exchange of aromatic residues Phe and Tyr, exchange of small amino acids Ala, Ser, Thr, Met and Gly However, it is not limited to these.

  Non-conservative substitution: The replacement of an amino acid residue with another non-biologically equivalent residue in a polypeptide. For example, substitution of one amino acid residue with another amino acid residue having a substantially different charge, substitution with another amino acid residue having substantially different hydrophobicity, or another having a substantially different spatial arrangement Substitution with amino acid residues.

  “Substituted amino acids” as used in the claims include substitute amino acids with both conservative and non-conservative substitutions. In addition to the 20 common amino acids normally found in naturally occurring polypeptides, trace amino acids such as canavanine, ornithine and 5-hydroxytryptophan and artificial amino acids, ie amino acids not normally found in vivo, such as t- Butylglycine can be used as an “alternative amino acid” in the present invention. Any chiral amino acid may be used.

  Diabetes: A condition in which cells cannot pass endogenous glucose across the membrane, either because of intrinsic deficiency of insulin and / or abnormal insulin sensitivity. Diabetes is a chronic disease in which metabolism of carbohydrates, proteins and fats is abnormal due to insufficient insulin secretion or target tissues being insulin resistant. There are two main forms of diabetes: insulin-dependent diabetes (IDDM, type I) and non-insulin-dependent diabetes (NIDDM, type II), differing in etiology, pathology, genetic nature, age of onset and treatment .

Both of the two major forms of diabetes are characterized by the inability to transport insulin at the appropriate time and in the amount necessary to control glucose homeostasis. Type I diabetes or insulin-dependent diabetes mellitus (IDDM) results from the destruction of beta cells and a lack of endogenous insulin levels. Type II diabetes or non-insulin dependent diabetes is caused by both abnormal body sensitivity to insulin and a relative deficiency in the ability to produce insulin.

  Food intake: The amount of food consumed by an individual. Food intake can be measured by volume or weight. For example, the food intake is expressed as the total amount of food consumed by the individual. Alternatively, food intake is expressed in terms of the amount of protein, fat, carbohydrate, cholesterol, vitamins, minerals or other food ingredients that an individual consumes. “Protein intake” means the amount of protein consumed by an individual. Similarly, “fat intake”, “carbohydrate intake”, “cholesterol intake”, “vitamin intake” and “mineral intake” are the amounts of fat, carbohydrates, cholesterol, vitamins and minerals an individual ingests, respectively. means.

  Hyperpolarization: A decrease in the membrane potential of a cell. Inhibitory neurotransmitters inhibit the transmission of nerve impulses via hyperpolarization. This hyperpolarization is termed inhibitory postsynaptic potential (IPSP). Although the threshold voltage of the cells does not change, a stronger excitatory stimulus is required for hyperpolarized cells to reach the threshold.

  Normal daily food intake: Average food intake taken by individuals of a specific species. Usually the daily diet can be displayed as caloric intake, protein intake, carbohydrate intake, and / or fat intake. A typical human daily diet generally includes the following: about 2000 calories, about 2400 calories, about 2800 to significantly more calories. In addition, a typical daily dietary dose for humans typically includes from about 12 g to about 45 g protein, from about 120 g to about 610 g carbohydrate, from about 11 g to about 90 g fat. A low calorie diet is less than about 85% of human normal caloric intake, and advantageously less than about 70%.

  In animals, calorie and nutrient requirements vary depending on the type and size of the animal. For example, in the case of cats, the total caloric intake per pound and the percent range of protein, carbohydrate and fat varies with the age and fertility of the cat. The general standard for cats is 40 cal / lb / day (18.2 cal / kg / day). About 30% to about 40% should be taken from protein, about 7% to about 10% from carbohydrates, and about 50% to about 62.5% from fat. One skilled in the art can readily identify the normal daily diet for any species of individual.

Obesity: A condition in which excess body fat is harmful to human health (Barlow and Dietz, Pediatrics 102: E29, 1998; National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Obes. Res. 6 (suppl. 2): 51S-209S, 1998). The balance between energy intake and energy consumption is lost, resulting in excess body fat. For example, the body mass index (BMI) may be used to evaluate obesity. One specified range well utilized, BMI of overweight if ^{25.0kg / m 2 ~29.9kg / m 2} , is obesity if BMI of 30kg / m ² or more.

As another rule, waist circumference dimensions are used to assess obesity. The measurement of abdominal excess fat is an important and independent method of assessing the various risks associated with obesity or overweight. Girth measurement is particularly useful for subjects classified as normal or overweight. In the measurement of the waist circumference, there is almost no predictability in addition to the classification of the risk of morbidity by BMI. Therefore, it is usually unnecessary to measure the waist circumference of an individual with BMI ≧ 35 kg / m ² . 40 inches (102c
m) Men with waistline dimensions greater than 35 and women with waistline dimensions greater than 35 inches (90 cm) are at increased risk of diabetes, dyslipidemia, hypertension and cardiovascular disease due to excess fat in the abdomen . Individuals with girth dimensions that exceed the above values should be considered in a higher risk range as defined by the BMI.

Evidence shows that obesity affects both morbidity and mortality.
For example, fat or obese individuals may have heart disease, non-insulin dependent diabetes mellitus (type II), hypertension, stroke, cancer (eg endometrial cancer, lung cancer, prostate cancer and colon cancer), dyslipidemia, They are at high risk for gallbladder disease, sleep apnea, hypofertility, osteoarthritis, and other diseases (see Lyznicki et al., Am. Fam. Phys. 63: 2185, 2001).

Fatty: An individual who shows a weight exceeding the ideal weight. Fat individuals may be obese but are not necessarily obese. For example, an overweight individual refers to any individual desiring to lose weight. According to one rule, a fat individual is a BMI of 25.0 kg / m ^{2 to} 29.9.
It is a kg / m ² individual.

  Polyethylene glycolation: a process in which poly (alkylene glycol), preferably activated poly (alkylene glycol), is reacted to obtain a covalent bond. For example, an amino acid such as lysine may be used as a promoter. “Polyethylene glycol addition” is often carried out using poly (ethylene glycol) or derivatives thereof, such as methoxy poly (ethylene glycol), although this term is used herein to refer to methoxy poly (ethylene glycol) It is not limited to use, but also includes the use of any useful poly (alkylene glycol), such as poly (propylene glycol). Polyethylene glycolation should be defined accordingly.

  Peripheral administration: Administration from other than the central nervous system. Peripheral administration does not include direct administration to the brain. Peripheral administration includes but is not limited to intravenous administration, intramuscular administration, subcutaneous administration, inhalation administration, oral administration, rectal administration, transdermal administration, buccal administration, sublingual administration, or intranasal administration. do not do.

  Polypeptide: A polymer in which a monomer is an amino acid residue bonded through an amide bond. If the amino acid is an α-amino acid, either the L-optical isomer or the D-optical isomer can be used, with the L-isomer being preferred. The term “polypeptide” or “protein” as used herein encompasses any amino acid sequence, including modified sequences such as glycoproteins. The term “polypeptide” specifically encompasses natural proteins and proteins produced recombinantly or synthetically. The term “polypeptide fragment” means a portion of a polypeptide, eg, a fragment having at least one sequence effective to bind to a receptor. The term “functional fragment of a polypeptide” means any polypeptide fragment that retains the activity of the polypeptide. Biologically functional peptides may include a fusion protein, which is a fusion of a peptide of interest with another peptide.

  Therapeutically effective amount: An amount sufficient to stop the progression of the disease or to regress the disease, an amount that can alleviate the signs or symptoms of the disease, or an amount that produces the desired result. In some examples, a therapeutically effective amount of a compound of the invention is an amount sufficient to inhibit or temporarily stop weight gain, an amount sufficient to reduce appetite, a caloric intake or An amount sufficient to reduce food intake or increase energy consumption, to reduce weight, or to reduce the risk of mortality or illness induced by a disease state It is.

Notes on naming: In the present specification, the oxm analog is named such that the amino acid sequence of the oxm analog is known from its name. “Oxm” means the wild type sequence of human oxm. If the oxm sequence is a region substituted with the corresponding exendin 4 sequence, it is described as “oxm (ex-15 to 27), and in this case, for example, residues 15 to 27 of oxm correspond to the exendin 4 Additional amino acid substitutions or terminal extensions are described as “Ser3-oxm”, where, for example, the third amino acid of oxm is replaced with serine. These two conventions relating to may be combined to form “Leu18-oxm (ex15-27).” When two conventions are used in combination, specifically named residues take precedence, for example “Leu18-oxm ( In ex15-27) ", residue 18 is Leu rather than Ala, the 18th residue of exendin.

  The inventors have surprisingly found that the analogs of the invention are effective appetite suppressants and / or have a continuous effect on food intake over native oxm and / or over native oxm. It has been found to be effective with respect to food intake. The analogs of the invention also exhibit longer half-lives or clearance times or are more resistant to degradation compared to oxm. To avoid the condition known as “escape”, it seems particularly important to extend the appetite suppression time. Short-term appetite suppressants can reduce appetite for the duration of one meal, and usually subjects do not consume much food on that meal. However, if the appetite suppressant has a short half-life, early clearance time, or the appetite suppressant is metabolized or otherwise removed from the subject's circulatory system, the subject will be “ The usual “appetite will be restored. Subjects who have eaten only a few meals during the previous meal time should actually have an increased appetite by the next meal time. When the subject satisfies the appetite, the food intake of the two meals may not be significantly reduced compared to the food intake when the appetite suppressant is not administered. In other words, the subject is considered to “retreat” from the effect of the appetite suppressant. The “withdrawal” can be reduced by additionally administering an appetite suppressant or using an appetite suppressant with a long action time. If the subject is restrained in appetite for a longer period of time, there is a practical limit to the total acceptable intake of food in each meal, so to the second meal that food that could not be consumed in the first meal can result The degree of desire is reduced. Repeated or continuous administration of the compound for a period of time, eg days or weeks, will suppress the appetite longer and reduce the likelihood of withdrawal from the appetite-suppressing effect.

  The improved activity and / or duration of action of oxm analogues over oxm provides various advantages. For example, appetite can be effectively suppressed with smaller doses (low doses and / or low maximum concentrations can be expected to reduce side effects (including nausea) and reduce treatment costs) And / or relatively powerful dosages can be used to achieve a strong realization. It is considered that the appetite suppressing effect of oxm and the induction of nausea occur through distinct distinct pathways. By selecting appropriate amino acid substitutions of the oxm molecule based on this assumption, it has good appetite suppressant activity, but is often induced, for example, by the use of the appetite suppressant exendin, which frequently induces nausea or in certain subjects It is believed that oxm analogs can be obtained that have reduced all or part of the recently reported nausea when using oxm at high doses. The specific compounds of the present invention used in the examples of the present specification exhibit an appetite suppression pattern represented by a “flatter blood concentration curve”, that is, the appetite suppression activity is exhibited more slowly than oxm. In some cases, the initial sharp peak (which may be related to nausea) is avoided, and in some cases the action time is extended.

  The oxm or oxm fragment herein which is a compound of the present invention, in particular the fragments X, X ′, Y and Y ′ of formulas (I), (II) and (III) are human oxm or human oxm fragments Is preferred. In another example, a porcine oxm or porcine oxm fragment.

The human oxm full length sequence (same as rat and hamster) is shown in SEQ ID NO: 7. Human oxm 1-14 is shown in SEQ ID NO: 8, which corresponds to the full length of human oxm with residues 15-37 removed. Human oxm1-26 is shown in SEQ ID NO: 9, which corresponds to the full length of human oxm minus residues 27-37. Human oxm 15 to 37 (SEQ ID NO: 1) corresponds to the total length of human oxm, excluding N-terminal residues 1 to 14. Human oxm 15-24 (SEQ ID NO: 3)
This corresponds to the total length of human oxm minus N-terminal residues 1-14 and C-terminal residues 25-37. Human oxm27-33 (SEQ ID NO: 5) corresponds to the total length of human oxm, excluding N-terminal residues 1-26 and C-terminal residues 34-37. Human oxm 34-37 is shown in SEQ ID NO: 10, which corresponds to the total length of human oxm minus the N-terminal residues 1-33. Human oxm 3-37 is shown in SEQ ID NO: 11, which corresponds to the full length of human oxm minus the N-terminal residues 1 and 2. The number indicating the position of the full-length oxm molecule starts from the N-terminus. Similar numbers are used for other fragments and variants of oxm described herein.

See Uesaka et al., “Glucagon-like peptide isolated from the eel intestine: effects on atrial beating”, Journal of Experimental Biology, 204, 3019-3026 (2001).
The oxm fragment of the molecule of the present invention may be an oxm derived from a species other than human and may be related to an oxm derived from a species other than human. Pig oxm sequences (which are the same as cows) and eel oxm sequences are shown as examples in Table 8 (SEQ ID NO: 12 and SEQ ID NO: 13 respectively). The oxm fragments of the molecules of the present invention may be derived from any of these sequences.

  The present invention specifically includes compounds of formula (I), wherein residues 15-37 are as defined in row A, provided that one or more of residues 15-37 defined in row A are Except that one or more of the 15th to 24th positions in row A are optionally substituted with the corresponding numbered residue in row R. If an extension moiety is present, the extension can comprise 1 to 6 amino acids, preferably 1 to 4 amino acids, in particular 2 amino acids. In a first preferred embodiment, the oxm analog of the invention comprises a first fragment corresponding to the N-terminal fragment of native oxm, a second fragment corresponding to the C-terminal fragment of native oxm and a first fragment. Oxm 15 to 24 (SEQ ID NO: 3) except that they are linked to each other and one or more amino acids or amino acid groups are substituted with the corresponding numbered amino acids of the following sequences: ) Including an intermediate fragment having a sequence;

(SEQ ID NO: 4)
Here, any said substitution occurs at the corresponding numbered position in oxm 15-24. Preferably, the first fragment comprises oxm1-x, where x is an integer from 14-23, such as 14-21, preferably 14-20, more preferably 14-18, especially 14. In a particularly preferred embodiment, the oxm analog is oxm1-14 sub15-24 oxm25-37, and sub15-24 means that all of the amino acids at positions 15-24 are replaced with SEQ ID NO: 4 as a whole. To do. Certain advantageous compounds include 3-10 sequence residues at positions 15-24 or between 15-24 of the oxm molecule starting at the N-terminus of SEQ ID NO: 4 Except for being substituted by a group, it has the full sequence of oxm. Substitution of 4 residues, eg 4 residues from oxm 15-18 to SEQ ID
Substitution with residues 1-4 of NO: 4 enhances and / or persists suppression of food intake as compared to saline (control) and oxm. Replacing 4 or more, for example 5, advantageously 6 and preferably 7 residues, the compound exhibits a stronger appetite suppressant activity. Particularly advantageous appetite-suppressing activity properties are obtained when 7-10 residues including oxm15 and starting with oxm15 are replaced with 7-10 corresponding sequence residues of SEQ ID NO: 4.

  For the S2 part of formula (II), the entire sequence in row D (SEQ ID NO: 4) corresponds to residues 15-24 of exendin 4. As described above, exendin 4 is known to have an appetite suppressive activity, but since it causes side effects of nausea when used, its effectiveness is limited (Buse et al., Diabetes Care, 27 (11), 2628-2635, 2004). The oxm analogs of the present invention have certain characteristics common to oxm (not nauseous or less nausea than exendin), while, as demonstrated herein, native oxm It is believed to show more sustained activity. Furthermore, exendin regions that show the beneficial appetite suppression effect of oxm are not inherently related to such effects.

  With respect to the Z part of any formula herein, Z may be an amino acid sequence consisting of any two amino acid residues following Gln, Asp or Glu, and Z is any two amino acids following Gln An amino acid sequence consisting of residues is preferred.

For the S2 part of formula (II), at least 3 amino acids in row C, such as at least 4
It is preferred that one amino acid, preferably at least 6 amino acids, in particular 7 to 10 amino acids, are substituted with the corresponding numbered amino acids in row D. Advantageously, the substituted amino acids comprise at least one sequence group comprising 2 or more amino acids, preferably at least one sequence group comprising at least 4 amino acids. Preferably, the substituted amino acids comprise a sequence group comprising no more than 10 amino acids. The substitution sequence group has 5 to 10 amino acids, for example 6 to 10 amino acids, preferably 7 to 10 amino acids, most preferably 8 to 10 amino acids, in particular 9 or 10 amino acids.

  Optionally, the oxm analogs of the invention may be further substituted with amino acid residues, wherein one or more amino acids or amino acid groups at positions 15-24 are the following sequences:

It may be substituted with the corresponding numbered amino acid of (SEQ ID NO: 145).

  With respect to the S2 part of formula (II), at least 3 amino acids of row A, such as at least 4 amino acids, preferably at least 6 amino acids, in particular 7-10 amino acids, corresponding amino acids of row R Is preferably substituted with. Advantageously, the substituted amino acids comprise at least one sequence group comprising 2 or more amino acids, preferably at least one sequence group comprising at least 4 amino acids. Preferably, the substituted amino acids have a sequence group comprising no more than 10 amino acids. The substitution sequence group has 5 to 10 amino acids, for example 6 to 10 amino acids, preferably 7 to 10 amino acids, most preferably 8 to 10 amino acids, in particular 9 or 10 amino acids.

Preferred compounds of the first preferred embodiment of the present invention described above are:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 14)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
15)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 16).
including.

  As a second preferred embodiment, the oxm analog of the present invention comprises a first fragment corresponding to the N-terminal fragment of native oxm, a second fragment corresponding to the C-terminal fragment of native oxm, and a first fragment. An intermediate fragment present between the second fragments and linking the first fragment and the second fragment to each other, said intermediate fragment having the sequence of oxm27-33 (SEQ ID NO: 5), one or A plurality of amino acids or amino acid groups are the following sequences:

It is substituted with the corresponding numbered amino acid of (SEQ ID NO: 6), said substitution optionally occurring at the corresponding numbered position of oxm27-33. Preferably, the first fragment comprises oxm1-y, where y is an integer from 26 to 32, preferably 26 to 30, in particular 26 or 30. In a particularly preferred embodiment, the oxm analog is oxm1-26sub27-33 oxm34-37, where sub27-33 has all amino acids at positions 27-33 as SEQ ID
NO: Indicates that the amino acid is substituted with the corresponding numbered amino acid of 6. Some preferred compounds have 4-7 amino acid residues starting at the N-terminus of SEQ ID NO: 6 at positions 27-33 or between positions 27-33 of the oxm molecule. It has an oxm sequence except that it is substituted with a group. Substitution of 4 residues, for example, substitution of oxm 27-30 with SEQ ID NO: 6 with residues 27-30 is more potent and / or persistent than saline (control) and oxm Reduce food intake. Substitution of 4 or more residues, for example substitution of 5, advantageously 6 and preferably 7 residues, further enhances the appetite suppression activity. Particularly advantageous appetite-suppressing activity properties are obtained when the seven sequence residues, including oxm27 and originating from oxm27, are replaced with seven sequence residues numbered with SEQ ID NO: 6 .

  For the S3 part of formula (III), the entire sequence in row F corresponds to residues 27-33 of exendin 4. As described above, exendin 4 is known to have an appetite suppressive activity, but since it causes side effects of nausea when used, its effectiveness is limited (Buse et al., Diabetes Care, 27 (11), 2628-2635, 2004). Furthermore, exendin regions that show the beneficial appetite suppression effect of oxm are not inherently related to such effects.

  Thus, with respect to the S3 part of formula (III), at least 3 amino acids of row E, such as at least 4 amino acids, preferably at least 6 amino acids, in particular 7 amino acids are numbered correspondingly in row F. It is preferably substituted with an amino acid.

  Advantageously, the substituted amino acids have at least one sequence group comprising 2 or more amino acids, preferably at least one sequence group comprising at least 4 amino acids. Preferably, it has a sequence group in which the substituted amino acid contains no more than 7 amino acids.

  The substitution sequence group has 3 to 7 amino acids, for example 4 to 7 amino acids, for example 4 amino acids, 5 amino acids, 6 amino acids or most preferably 7 amino acids.

  The variants are as described above for the first embodiment.

Preferred compounds of the second embodiment of the invention are the following sequences:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 17)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO
: 18)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 19)
A compound having

A third preferred embodiment of the present invention includes compounds of formula A ¹ -A ³ -oxm4-r, where r is 15 to 37 and A ¹ is an amino acid other than His (particularly D-histidine). Yes, A ² is Ala or Ser, and A ³ is Glu, Asp or Gln. Said “His”
"Described before to mean D- histidine" unless specified explicitly with a D- ", should be understood to mean L- histidine. Preferably, A ¹ -A ^3- is D-His-Ala-Asp-, D-His-Ser-Asp-, D-His-Ala-Glu-, D-His-Ser-Glu-, D-His-Ala-Gln- or D- It means His-Ser-Gln.

In a particularly preferred embodiment of the invention, the oxm analog has two or more of the following characteristics:
(I) one or more substitutions are present at or between positions 15-24 of oxm as defined in formula (II);
(Ii) one or more substitutions are present at or between positions 27-33 of oxm as defined in formula (III);
(Iii) Z is D-His-Ser-Asp-, D-His-Ala-Asp-, His-Ala-Asp-, D-His-Ala-Glu-, D-His-Ser-Glu-, D- Representing His-Ala-Gln- or D-His-Ser-Gln-;
(Iv) position 18 is L-leucine; and (v) the extension has 1 to 5, for example, 2 amino acids prior to position 38.

For example, a first preferred group of oxm analogues combines the features of (i) and (iii). A second preferred group of oxm analogues combines the features of (ii) and (iii). Another suitable group of oxm analogs has all the features of (i) and (iii) or (i), (ii), (iii) above. Accordingly, certain suitable analogs are of formula (IV):
ZX-S2-Trp-Leu-S3-Y '(IV)
Z and X are as defined in formula (I), S2 is as defined in formula (II), S3 and Y ′ are as defined in formula (III), and The preferred properties of Z, S2 and S3 defined in I), (II) and (III) apply to the above formula as well.

  Further particularly preferred oxm analogues of the present invention, and particular analogues of any suitable said embodiment (including particularly preferred embodiments) are extensions consisting of preferably two amino acids at positions 38 and 39. It may be advantageous to include a part. In one advantageous embodiment, the extension is -Pro-Ser. In another advantageous embodiment, the extension is -Ala-Ala. Other preferred examples include -Ala-Ala-Lys; and -Ala-Ala-Glu-Glu-Lys. The compounds of the invention may feature an extension combining all of examples (i) and / or (ii) and / or (iii), in particular all (i) to (iii). It is believed that the presence of the extension would protect against degradation, resulting in a slower degradation rate of the analog and a longer half-life.

  In a fourth embodiment of the invention, the oxm analog of formula (I) comprises oxm 1-26 as the N-terminal fragment, and oxm residues 27-37 are substituted with the corresponding numbered amino acids in row B above. Yes.

  Although described for purposes of accuracy, if substitution occurs at positions 22 and / or 28, at least one, and preferably two or more other amino acids will also be substituted.

The invention also provides a general formula:
Z-X-S4-S5-E (V)
Represented by
X is oxm4-14,
Z is an amino acid sequence consisting of three amino acid residues, for example, having any suitable property as described above for Z in general formula I,
S4 is the sequence Glu Glu Glu Ala Val Arg Leu Phe Ile Glu (SEQ ID NO: 35) containing the sequence Asp Ser Arg Arg Ala Gln Asp Phe Val Gln (SEQ ID NO: 35). Optionally comprising the sequence Arg Ile Glu Ile Val Lys Tyr, comprising 1 to 10 amino acids present in the corresponding position of ID NO: 4)
Includes 0-9 amino acids present in corresponding positions of Phe Val Gly (SEQ ID NO: 145) and 0-5 different from amino acids present in corresponding positions of SEQ ID NO: 4 and SEQ ID NO: 35 A sequence consisting of 10 amino acids, including 1 amino acid,
S5 replaces at least one residue at positions oxm 25-37 or 27-33 with the sequence Lys (27) Asn (28) Gly (29) Gly (30) Pro (31) Ser (32) Ser (33) (SEQ ID NO: 24) oxm 25-37 substituted with one or more residues numbered correspondingly;
E means any extension having one or more amino acid residues, for example any extension described as a suitable extension of formula I, a variant or derivative thereof, or a salt or A solvate is provided.

In Formula V, S4 preferably comprises at least three amino acids present in the corresponding position of SEQ ID NO: 4, and as one advantageous example, S4 corresponds to SEQ ID NO: 4 and SEQ ID NO: 35. At least one amino acid that is different from the amino acid number. Preferably, S4 comprises at least 6 amino acids present in the corresponding position of SEQ ID NO: 4 and at least one amino acid different from the corresponding numbered amino acids of SEQ ID NO: 4 and SEQ ID NO: 35 . More preferably, S4 comprises 9 amino acids present in the corresponding position of SEQ ID NO: 4 and at least one amino acid different from the corresponding numbered amino acids of SEQ ID NO: 4 and SEQ ID NO: 35 . The inventors have found that on many of these compounds the onset of appetite suppression activity is delayed more than the other compounds of the invention (SEQ ID NO: 16 and SEQ ID NO: 7), which In particular, it offers the advantage that the compound can be administered in higher doses than for example oxm alone (and therefore lasts longer), resulting in a so-called “rapid nausea”, ie a higher blood concentration of the active peptide immediately after administration The superior effect of lowering the likelihood of the initial induced nausea and / or more rapid weight loss is achieved. Compounds that exhibit this aspect of the invention include, for example:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
31)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Ile Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 32)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Leu Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 34)
It is.

  In particular, the peptides SEQ ID NO: 31 and SEQ ID NO: 34 cause an advantageous delay in the onset of the activity.

  According to an embodiment of the invention of formula VI, X is 1, 2, 3, 4 or 5 amino acids or 5 or more amino acids, for example 5-10 or 5-20 amino acids, Good. X may be Ala-Y, where Y is optionally one or more amino acids or absent.

Another example of a compound of the present invention includes
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Lys Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Asp Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Gln Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Lys Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Ile Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Ser Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Arg Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Leu Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Gln Gln Val Ile Arg Ile Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys; D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Ar
g Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala;
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-lauroyl Asn Asn Ile Ala;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala; D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala; D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val-palmitoyl Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala; D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-palmitoyl;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-palmitoyl;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-lauroyl;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-palmitoyl;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-lauroyl;
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys-palmitoyl Asn Asn Ile Ala Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Lys; His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Ala Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Tyr; His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys-dodecyl Arg Asn Arg Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-dodecyl Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala
Is included.

  The invention further includes forms that reflect the sequences disclosed in the accompanying examples and / or drawings.

Variants Oxm herein includes oxm variants. One or more oxm fragments are incorporated into the oxm analogs of the present invention, especially in the fragments oxm1-14, oxm1-26, oxm3-37, oxm4-37, oxm34-37 and oxm25-37. A fragment selected from the group consisting of, but not limited to: The oxm or oxm fragment may be a variant of native oxm or a variant of native oxm fragment, such as a variant of native human oxm or a native human oxm fragment, or native porcine oxm or native porcine oxm. It may be a variant of a fragment. Variants include oxm molecules or oxm fragments with deletions, insertions, inversions, repeats and substitutions (eg, conservative substitutions and non-conservative times; see, eg, Table 8 below). The molecule retains at least some activity of the corresponding non-mutated oxm molecule or fragment. More than one amino acid (eg, 2, 3 or 4) may be replaced with another amino acid. Preferably at least 70%, for example at least 80%, in particular at least 90% of the oxm fragment identified by any of the formulas (I), (II) and (III), in particular the amino acid of X, X ′, Y or Y ′ Corresponds to the amino acid of the native oxm fragment. The four amino acids on the C-terminal side of the native oxm are preferably all present in the molecule of the present invention. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids present at positions 3-37 may be substituted with alternative amino acids.

  Typical conservative substitutions are reciprocal substitution between aliphatic amino acids Ala, Val, Leu and Ile, exchange of Ser and Thr with hydroxy groups, exchange of acidic residues Asp and Glu, amide residues Exchange of Asn and Gln, exchange of basic residues Lys and Arg, exchange of aromatic residues Phe and Tyr, exchange of small amino acids Ala, Ser, Thr, Met and Gly. Guidelines for how to form amino acid substitutions that do not affect the phenotype, ie, substitutions that do not change the expressed phenotype, are described by Bowie et al. (Science 247: 1306-1310, 1990).

  Oxm or oxm fragment variants include one or more amino acids (eg 2, 3, 4, 5, 6, 7 or 8) of one oxm at the same position in oxm from different species. Also included are variants that are substituted with an existing amino acid. The sequences of human oxm and porcine oxm are shown in Table 12 above. In particular, variants of human oxm or porcine oxm include one or more amino acids (eg, 2, 3 or 4) of human oxm or porcine oxm in the same position of oxm from different species Variants that are substituted with are included.

  Here, variants of native human oxm are described. A variant may be part of a molecule that is not essentially derived from an oxm sequence. Such mutants can exist as well as mutants described as oxm.

  Although the amino acids herein are preferably natural amino acids, the sequences or fragments herein may include one or more non-natural amino acids, if desired.

  Although described for the sake of accuracy, those shown herein below as formula (I) include those of formula (II) or formula (III) or formula (IV) or formula (V) or formula (VI ) As well as any other suitable examples of compounds described above.

It is preferred that the mutant compound retains at least some of the activity of the corresponding non-mutant compound.

  More preferably, the mutant compound exhibits a stronger appetite suppression activity than the corresponding non-mutant compound.

Derivatives The compounds of the invention undergo amidation, glycosylation, carbamylation, alkylation, acylation, eg acetylation, sulfation, phosphorylation, cyclization, lipidation, protein (eg albumin) conjugation and polyethylene glycolation. The structure of formula (I) modified by known methods can be included. The structure of formula (I) may be modified at random positions in the molecule or at specific positions in the molecule and may have 1, 2, 3 or more chemical binding sites.

  The compound of the present invention may be a fusion protein, wherein the structure of formula (I) is fused with another protein or polypeptide (fusion partner) by a conventionally known recombinant method. Such a fusion protein can be synthesized using a known synthesis method. Such fusion proteins include the structure of formula (I). Any suitable peptide or protein may be used as a fusion partner (eg, serum albumin, carbonic acid dehydrogenase, glutathione-S-transferase, single chain antibody, antibody, antibody fragment or thioredoxin, etc.). For example, the compounds of the present invention can be fused to an immunoglobulin light chain variable region that specifically binds serum albumin, as described in WO 05/118642. Suitable fusion partners will not exhibit a biological reaction in vivo. Such a fusion protein can be formed by linking the carboxy terminus of the fusion partner to the amino-terminus of the structure of formula (I), and vice versa. In addition, a cleavable linker may be used to bind the structure of formula (I) to the fusion partner. The resulting cleavable fusion protein is cleaved in vivo to release the active form of the compound of the invention. Examples of such cleavable linkers include, but are not limited to, linkers DDDDY, GPPR, AGGG, and HPPFHL. Instead, the cleavable linker can be cleaved with enterokinase, thrombin, ubiquitin cleaving enzyme and renin, respectively. See US Pat. No. 6,410,707.

  The compounds of the present invention also have a fusion partner attached to the structure of formula (I) via a disulfide bond and are shared between at least one Cys residue of the compound of the present invention and at least one Cys residue of the fusion partner. It may be a fusion protein such that a bond is formed.

  When using a protein as a fusion partner, it is preferable to select a protein that does not exhibit undesired antigenicity. Undesirable antigenicity can be avoided by selecting the allogeneic protein of the animal to which the compound is administered.

  The compounds of the present invention may be physiologically functional derivatives having the structure of formula (I). The term “physiologically functional derivative” as used herein means a chemical derivative of a compound of formula (I) that has the same physiological function as an unmodified compound of formula (I). For example, physiologically functional derivatives can be converted in the body to compounds of formula (I). According to the invention, examples of physiologically functional derivatives include esters, amides and carbamates, with esters and amides being preferred.

The esters and amides of the compounds of the present invention with a pharmaceutically acceptable, appropriate site, binds, for example, acid groups, C _{1 to 6} alkyl -, C _{5 to 10} aryl -, C _{5 to 10} Al - C _1-6 alkyl-, or amino acid-ester or -amide may be included.

The acyl side chain is considered advantageous because its lipophilicity causes the components to bind to albumin and greatly reduce the clearance rate from the subject, thus extending the half-life and shelf life. Acyl side chains of the low molecular weight acyl, for example C ₁ -C ₉ acyl, especially be a C _{1 to 6} acyl, C ₄ -C ₄₀ acyl are preferred, especially C _{8 to 25} acyl, more particularly C ₁₆ acyl or C ₁₈ Acyl is preferred. Palmitoyl is particularly preferred as the acyl side chain, as is lauroyl. The acyl side chain can be added at any position in the peptide backbone. The acyl substituent may be bonded to the amino acid residue such that the carboxyl group of the acyl substituent forms an amide bond with the amino group of the amino acid residue. The acyl substituent may be bonded to the amino acid residue such that the amino group of the acyl substituent forms an amide bond with the carboxyl group of the amino acid residue. In a more preferred embodiment, the present invention relates to an oxm derivative in which an acyl substituent is attached to the parent peptide via a spacer. For example, the acyl substituent can be attached to the oxm component via a spacer, where the carboxyl group of the spacer forms an amide bond with the amino group of the oxm component. It is particularly preferred that an acyl side chain is added (optionally via a spacer) at a position where a lysine residue is present in the peptide backbone. This is because lysine having four carbon atom side chains whose ends are ε-amino groups can particularly easily add an acyl side chain. A lysine residue may need to be introduced into the sequence only to form a site suitable for adding an acyl side chain. Alternatively, the acyl side chain may be added to a lysine residue prior to peptide synthesis, so that the acyl side chain is incorporated in a suitable synthesis step and direct acylation occurs. This method is advantageous when the peptide sequence contains one or more lysine residues, as it eliminates the need for selective conditions such that only the specific lysine of interest is acylated. The peptide derivatives preferably have 3, more preferably 2, and most preferably 1 acyl side chain substituents. Examples of acyl groups (and other lipophilic substituents), means for attaching them to peptides and special synthetic methods (with or without the use of spacers) are described in US Pat. No. 6,268,343 and US Pat. 458,924.

  According to certain preferred embodiments, acyl side chains are added at positions 30 and / or 33 and / or 39 and / or 40 of the peptide backbone.

The amide and carbonate compounds in the pharmaceutically-acceptable a certain formula (I), a suitable position, to bind to, for example, amino group, C _{1 to 6} alkyl -, C _{5 to 10} aryl -, C _{5 to 10} Al- _C1-6alkyl- , or amino acid-ester or -amide, or -carbamate is included.

Lipidization of sulfhydryl-containing compounds with fatty acid derivatives is described in US Pat. No. 5,936,092; US Pat. No. 6,093,692; and US Pat. No. 6,225,445. . Fatty acid derivatives of the compounds of the invention, including those of the invention that bind to fatty acids through disulfide bonds, can be used to transport the compounds of the invention to neurons and tissues. Lipidation greatly increases the absorption of the compounds of the present invention compared to the absorption rate of the corresponding non-lipidated compound, prolonging the blood and tissue residence time of the compound. Furthermore, since the disulfide bond in the lipidated derivative is relatively unstable in the cell, the molecule is easily released into the cell from the fatty acid component. Suitable lipid-containing components are hydrophobic substituents having 4 to 26 carbon atoms, preferably 5 to 19 carbon atoms. Suitable lipid groups include, but are not limited to, palmityl (C ₁₅ H ₃₁ ), oleyl (C ₁₅ H ₂₉ ), stearyl (C ₁₇ H ₃₅ ), cholate and deoxycholate.

  Those of skill in the art will recognize that certain amino acid residues may be introduced into the oxm sequence in order to readily realize one or more of the modification methods described herein.

Cyclization methods include cyclization by forming disulfide bonds and head-to-tail cyclization utilizing a cyclization resin. The cyclized peptide is believed to have improved stability and more resistance to enzymatic cleavage, thereby constraining the conformation. Cyclization is particularly advantageous when the acyclic peptide has a cysteine group at the N-terminus. Suitable cyclized peptides include monomeric and dimeric head-to-tail cyclized structures. The cyclized peptide can contain one or more additional residues, especially including side chains that are incorporated for cyclization using additional cysteines or resins that are incorporated to form disulfide bonds. Can do.

  The compound of the present invention may be a polyethylene glycol adduct of formula (I). Polyethylene glycolated compounds of the present invention can provide additional benefits such as improving the solubility and stability of the polypeptide, extending circulation time, and reducing immunogenicity (US Pat. No. 4,179). 337).

The chemical component for derivatization of the compounds of the present invention may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polymer component for derivatization of the compounds of the present invention can be any branched or unbranched polymer having any molecular weight. For ease of handling and manufacture, the preferred molecular weight of polyethylene glycol used in derivatization of the compounds of the present invention is from about 1 kDa to about 100 kDa, and the term “about” refers to several molecules in the preparation of polyethylene glycol. Will be greater or less than the stated molecular weight. Desired therapeutic content, e.g. desired sustained release time, effects on any biological activity, ease of handling, degree of antigenicity or lack of antigenicity, other of polyethylene glycol for therapeutic proteins or analogs Depending on the known effects, polymers with different molecular weights may be used. For example, polyethylene glycol has an average molecular weight of about 200, 500, 1,000, 1,500, 2,000, 2500, 3000, 3,500, 4000, 4,500, 5 , 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8.0
00, 8,500, 9,000, 9,500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,
500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, It has 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000 or 100,000 kDa.

  Salts and solvates of the compounds of the invention suitable for use in medicine are those in which the counterion or the solvent in combination is pharmaceutically acceptable. However, salts and solvates having counterions or solvents that are not pharmaceutically acceptable may also be used, for example, in the preparation of compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof. It can be said that it is a category of the present invention.

Salts suitable for the present invention are those formed with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, hydrogen peroxide. Chloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfone Included are those formed using acids and isethionic acids. Another acid, such as oxalic acid, is not pharmaceutically acceptable per se, but as an intermediate in the preparation of the compounds of the present invention and pharmaceutically acceptable salts of the compounds of the present invention. It is considered useful. Pharmaceutically acceptable salts using bases include ammonium salts, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, salts using organic bases such as Dicyclohexylamine and N-methyl-D-glucomine are included.

  Those skilled in the field of organic chemistry recognize that many organic compounds form complexes with solvents, and the complexes react in, or precipitate from, and crystallize from the solvent. There will be. Such complexes are known as “solvates”. For example, a complex with water is a “hydrate”. The present invention provides solvates of the compounds of the present invention.

  The peptide of the present invention is produced by any suitable technique related to peptide synthesis including conventional techniques, but is not limited thereto. Examples of the conventional techniques include synthesis from individual amino acids, particularly sequential synthesis using an automatic peptide synthesizer. Native peptide modification or recombinant synthesis techniques.

Symptoms The present invention also provides a pharmaceutical used to control appetite, eating, food intake, energy consumption, caloric intake, said pharmaceutical containing an effective amount of a compound of the present invention. More particularly, the present invention relates to a pharmaceutical used for the treatment of obesity, a pharmaceutical used for the treatment of eating disorders, a pharmaceutical used for the treatment of diabetes or symptoms of diabetes, or the treatment or prevention of complications associated with obesity or overload. Provide medicinal products to use.

  The present invention also provides a method of reducing excess body weight, for example aesthetically excess body weight, said method comprising administering an effective amount of a compound of the invention to a subject who wishes to lose weight.

  The present invention further provides a method of treating a condition selected from obesity, eating disorders and diabetes, said method comprising the step of administering an effective amount of a compound of the present invention to a subject in need of treatment of said condition. .

  The invention also includes obesity, eating disorders, diabetes, heart disease, hypertension, lipid disease and other gastrointestinal motor activity and gastrointestinal functions, such as impaired water absorption and fluid transport, or pancreatic endocrine glands The present invention relates to the use of a compound of the present invention in the manufacture of a drug for treating a disorder of hepatobiliary function, a drug for treating a disorder of hepatobiliary function or a drug for preventing cancer. The present invention further relates to a compound of the invention in the manufacture of a medicament for use in controlling any one or more items selected from appetite, eating, food intake, energy expenditure and caloric intake About the use of.

  The subject to whom the compound is administered may be overweight, such as obesity. Alternatively or additionally, the subject may have diabetes that is insulin resistant or glucose intolerant, or both. The subject may be diabetic, for example, the subject may be type II diabetes. The subject may be overweight, such as obesity, and may be diabetic, such as type II diabetes.

  In addition or alternatively, the subject may be suffering from or at risk of suffering from a condition in which obesity or fatness is a risk factor. Such diseases include cardiovascular diseases such as hypertension, atherosclerosis, congestive heart failure, and dyslipidemia; stroke; gallbladder disease; osteoarthritis; sleep apnea; For example, multiple cystic ovary syndrome; cancer such as lung cancer, prostate cancer, colon cancer, endometrial cancer, renal cancer and esophageal cancer; varicose veins; black epidermoma; eczema; exercise intolerance; insulin resistance; Hypercholesterolemia; cholelithiasis; osteoarthritis; orthopedic disorders; insulin resistance such as type II diabetes and X syndrome; metabolic syndrome; and thromboembolism (Kopelman (2000)) , Nature 404: 635-43; Rissanen et al., British Med. J. 301, 835, 1990).

  Other diseases related to obesity include depression, anxiety, panic attacks, migraine, PMS, chronic pain, fibromyalgia, insomnia, impulsivity, obsessive-compulsive disorder, irritability Intestinal syndrome (IBS), clonic convulsions are included. Furthermore, obesity is known to be a risk factor that increases the incidence of common numbness (see Kopelman, Nature 404: 635-43, 2000). In general, obesity shortens lifespan and poses a significant risk of simultaneously suffering from such diseases.

  Other diseases or disorders associated with obesity include birth defects, maternal obesity that increases the incidence of neural tube defects, carpal tunnel syndrome (CTS); chronic venous insufficiency (CVI); daytime sleepiness; Venous thrombosis (DVT); End stage renal disease (ESRD); Gout; Heart disease; Immune response disorder; Respiratory dysfunction; Infertility; Liver disease; Lower back pain; Black epidermoma; Endocrine system abnormalities; Chronic hypoxia and hypercapnia; Skin effects; Elephant dermatosis; Gastroesophageal reflux; Radius spines; Edema of the lower limbs; Breast hypertrophy leading to a number of problems such as neck pain, chronic odor from skin overlapping the folds of the lower breast and infection of the skin; large anterior abdominal wall mass For example, abdominal subcutaneous lipohistitis with frequent subcutaneous lipohistitis, impending gait, frequent infections, odor, difficulty wearing clothes, lower back pain; musculoskeletal disease; pseudo-brain tumor (or benign brain pressure) Hypertension), and sliding hiatal hernia.

  The present invention further provides a method for increasing the energy consumption of a subject. The method includes, for example, peripherally administering to a subject a therapeutically effective amount of a compound of the present invention to alter energy expenditure. Energy burns in every physiological process. By changing the efficiency of such processes and changing the number and nature of process invocations, the body can directly change the rate of energy consumption. For example, during digestion, food travels through the intestines and the food is digested, so the body consumes energy, and within the cell, it can alter cellular metabolic efficiency to produce more or less heat. it can.

  In one aspect, the method of the present invention includes an operation of an arcuate circuit that changes the food intake in conjunction and changes the energy consumption accordingly. Energy expenditure is the result of cellular metabolism, protein synthesis, metabolic rate, and calorie utilization. Thus, in aspects of the invention, administration of a compound of formula (I) increases energy expenditure and reduces calorie utilization efficiency.

  The present invention also provides a method of improving a subject's lipid profile. The present invention also provides a method for alleviating a symptom or disorder that can be alleviated by reducing the digestibility of nutrients.

  Appetite can be measured by any method known to those skilled in the art. For example, a decrease in appetite can be determined by psychological evaluation. For example, administration of a compound of the invention alters the perceived hunger, satiety, and / or satiety. The feeling of hunger can be measured by any method known to those skilled in the art. For example, hunger can be determined by evaluating hunger and sensory perception using psychological assays such as a survey table. The survey table may be, for example, a visual analog score (VAS) survey table, but is not limited thereto. As an example, hunger is evaluated by answering questions about food and beverage requirements, expected food intake, nausea, smell and taste recognition, but is not limited thereto.

The compounds of the present invention may be used for the purpose of controlling or treating body weight, for example inhibiting or preventing obesity, in particular one or more of the following: inhibiting and reducing weight gain; inducing and promoting weight loss; Reduction of obesity status as judged by body mass index. In order to control one or more of appetite, satiety and fasting with a compound of the invention, in particular:
One or more items may be used to practice: reduction, suppression and inhibition of appetite; induction, increase, enhancement and promotion of satiety and satiety; reduction, inhibition and suppression of hunger and hunger. The compounds of the present invention may be used to maintain one or more of desirable body weight, desirable body mass index, desirable appearance and good health.

  The subject may be a subject who wishes to lose weight, for example, a female or male subject who wishes to change his appearance. The subject may wish to feel less hungry, for example, the subject may be a person engaged in a long-term task requiring high concentration, such as an active military officer, air traffic controller, or long-distance truck driver. It's okay.

  The present invention may be used to treat, prevent, ameliorate or alleviate symptoms or disorders that develop, coexist or worsen due to the relatively high digestibility of nutrients. As used herein, “a symptom or disorder that can be alleviated by a decrease in the digestion and absorption rate of calories (or nutrients)” refers to the onset, concomitant or worsening due to the relatively high digestion and absorption rate of nutrients. Or any symptom or disorder of a subject that can be alleviated, for example, by reducing the digestibility of nutrients by reducing food intake. Subjects with insulin resistance, glucose intolerance, or any form of diabetes, such as type I, type 2 or gestational diabetes, may also benefit from the methods of the invention.

  Symptoms or disorders resulting from increased caloric intake include, but are not limited to, insulin resistance, glucose intolerance, obesity, diabetes, including type II diabetes, eating disorders, insulin resistance syndrome, and Alzheimer's disease. do not do.

  According to the invention, the compound of formula (I) is preferably used for the treatment of humans. However, although the compounds of the invention are commonly used to treat human patients, other vertebrates exhibiting similar or identical symptoms, such as other primates; livestock, such as pigs, cows and birds; It may be used to treat competing animals such as horses; pet animals such as dogs and cats.

Compositions While it is possible to administer the active ingredient alone, it is preferred to include the active ingredient in the formulation or medicament. Accordingly, the present invention provides a formulation comprising a compound of formula (I) or said variant or derivative of a compound, or a salt or solvate thereof, and a pharmaceutically acceptable additive. The medicament of the present invention can be administered in the dosage forms described below.

  The preparations of the present invention include oral administration, parenteral administration (including subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration, and intra-articular administration), inhalation administration (a variety of sprayed aerosols of a predetermined amount). , Including particulate dust or mist generated using nebulizers or syringes), rectal and topical administration (dermal, transdermal, transmucosal, buccal, sublingual, and intraocular) However, the optimal route of administration may vary depending on, for example, the condition and disorder of the patient being administered.

  The formulation is conveniently in the form of a unit dose and can be prepared by any method well known in the pharmaceutical arts. Both methods include the step of bringing the active ingredient into association with a pharmaceutical carrier which contains one or more accessory ingredients. In general, the formulations are prepared by uniformly or intimately combining the active ingredient with liquid carriers or fine solid carriers or both, and then, if necessary, bringing the product into the desired dosage form.

Formulations according to the present invention suitable for oral administration may be individual units such as capsules, cachets or tablets each containing a predetermined amount of active ingredient; may be powders or granules; It may be a solvent or suspension in an aqueous solution; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may be a bolus, electuary or paste. Various pharmaceutically acceptable carriers and their formulation are described in standard pharmaceutical literature, such as Remington's Pharmaceutical Sciences (EW Martin). See also Wang, YJ and Hanson, MA, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42: 2S, 1988.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are made by mixing the flowable active ingredient, such as powders or granules, optionally with binders, lubricants, inert excipients, lubricants, surfactants or dispersants, and compressing with a suitable machine. May be manufactured. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid excipient. The tablets can be optionally coated or scored and can be formulated so that the active ingredient contained in them is released slowly or in a controlled manner. The compounds of the invention are administered, for example, in dosage forms suitable for immediate release or persistence. Immediate release or persistence can be obtained by using a suitable pharmaceutical comprising the compound of the present invention, and in particular, persistence can be obtained by using a subcutaneous implant or an osmotic pump. When the compound of the present invention is mixed with a transport aid or carrier and formulated for oral administration, therapeutic polymers and highly charged compounds are particularly likely to pass through the cell membrane of the small intestine. Such transport aids or carriers can further prevent the peptide from being enzymatically degraded as it passes through the gastrointestinal tract (GI) and / or additional agents that protect the formulation from such degradation. Can be contained. The compounds of the present invention may be administered by the liposome method.

  Examples of orally administered pharmaceuticals include, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickening agent, sweeteners or flavoring agents known in the art Suspensions which can be made; for example microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other additives, binders, extenders, disintegrants, excipients known in the art Immediate-release tablets that can contain an agent and a lubricant. Compounds of formula (I) may be transported through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or lyophilized tablets are examples of dosage forms that can be used. Examples of pharmaceutical agents include those in which a compound of the present invention is formulated with an instantly soluble excipient such as mannitol, lactose, sucrose and / or cyclodextrin. Such formulations may include high molecular weight additives such as cellulose (Avicel) or polyethylene glycol (PEG). Such formulations also adjust additives such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic anhydride copolymer (eg Gantrez) and release aids that help adhere to mucous membranes Agents, such as polyacrylic acid copolymers (eg Carbopol 934). Lubricants, glidants, flavoring agents, colorants and stabilizers may be added to facilitate manufacture and use.

Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may include antioxidants, buffers, bacteriostats, and solutes to make the formulation isotonic with the blood of the subject patient; Aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents. Formulations may be in single or multi-dose containers, such as sealed ampoules and vials, frozen to the point where a sterile liquid carrier, such as saline or water for injection, may be added immediately before use. Can be stored dry (lyophilized). Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets as described above. Examples of pharmaceuticals administered parenterally include, for example, suitable non-toxic parenterally administrable excipients or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic saline, or another Injectable solutions or suspensions which may contain suitable dispersing or wetting agents and suspending agents (including synthetic mono- or diglycerides), fatty acids (including oleic acid), or Cremaphor. The aqueous carrier has, for example, a pH of 3.0 to 8.0, preferably a pH of 3.5 to 7.4, such as 3.5 to 6.0, such as 3.5 to about 5.0, etc. It may be a tonic buffer. Useful buffers include sodium citrate-citrate buffer, sodium phosphate-phosphate buffer, and sodium acetate / acetic acid buffer. The compounds are preferably free of oxidants and other compounds known to be harmful to oxm and oxm agonists.

  Additives that can be included are, for example, other proteins, such as human serum albumin preparations or plasma preparations. If desired, the medicament may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives and pH buffering agents and the like such as sodium acetate or sorbitan monolaurate.

  Examples of pharmaceuticals for nasal aerosol or inhalation administration include, for example, benzyl alcohol or other suitable preservatives known in the art, absorption enhancers to increase bioavailability, and / or other solubilizers or Examples include a solution in saline solution that may contain a dispersing agent. In order to be suitable as a nasal aerosol or pharmaceutical for inhalation administration, the compounds of the invention are transported in the form in which the aerosol is nebulized from pressurized packages or nebulizers, with suitable propellants such as dichlorodifluoro- Methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas is utilized. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that can transport a metered amount. For use in an inhaler or insufflator, gelatin capsules and cartridges, for example, may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. In one embodiment, the compounds of the invention are administered as an aerosol from a valve that transports a metered dose via an aerosol adapter, also known as an actuator. It may also include stabilizers and / or porous particles that allow transport to the deep lung (see US Pat. No. 6,447,743). Intranasal formulations may contain a transport agent that reversibly opens the nasal adhesion zone, which increases the permeability of the agent (see US Patent No. 10 / 322,266).

  Formulations for rectal administration may be retention enemas or suppositories containing useful carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are generally solid at room temperature, but liquefy and / or dissolve in the rectum to release the drug.

  For preparations for topical administration in the mouth, such as buccal or sublingual administration, lozenges, gelatin and glycerin or sucrose and arabic containing sucrose and a flavoring base such as gum arabic or tragacanth A pastry tablet containing an active ingredient in a base such as rubber is included. An example of a composition for topical administration is a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

  Preferred single dose formulations are those containing the active ingredient in an effective amount as described above, or an appropriate portion thereof.

  It should be understood that in addition to the components specifically mentioned so far, the formulations of the present invention can contain other drugs commonly used in the field depending on the type of formulation in question, eg suitable for oral administration The formulation may include a flavoring agent.

The compounds of the invention are also suitable for administration as a sustained release system. Examples of suitable sustained release systems of the present invention include suitable polymeric materials, such as semipermeable polymer matrices in the form of shaped articles such as films, or microcapsules; for example as usable emulsions in oil Suitable hydrophobic materials; or ion exchange resins; and slightly soluble derivatives of the compounds of the invention, for example, slightly soluble salts. Sustained release systems include oral administration; rectal administration; parenteral administration; intravaginal administration; vaginal administration; intraperitoneal administration; Or it can be administered as an oral or nasal spray.

  The administrable agent is suitably formulated so that the release of the compound of the invention can be controlled. For example, a pharmaceutical agent can change the interfacial properties of biodegradable polymers, polysaccharides, softening polymers and / or bioadhesive polymers, amphiphilic polymers, compound particles of formula (I) The particle form may include one or more of the following. Since these pharmaceuticals have a certain biocompatibility, the release of the active ingredient can be controlled. See US Pat. No. 5,700,486.

The compounds of the present invention can be pumped (Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201, 1987; Buchwald et al., Surgery 88: 507, 1980; Saudek et al., N. Engl. J. Med 321: 574, 1989), or by continuous subcutaneous infusion, eg using a minipump. Bag solutions for intravenous administration can also be used. The result obtained by measuring the loss of total body weight or the ratio of fat to lean body mass, or another that the physician considers appropriate to measure the control or prevention of obesity or the prevention of symptoms associated with obesity The result obtained by the criteria is an important factor in selecting an appropriate dose. Another controlled release system is discussed in the journal by Langer (Science, 249: 1527-1533, 1990). As an alternative to the disclosed embodiment, the compounds of the present invention can be delivered using an implanted pump, eg, US Pat. No. 6,436,091; US Pat. No. 5,939,380; US Pat. No. 5,993,414.

  An implantable drug infusion device can be used to dose or infuse a patient with a drug or any therapeutic agent over a long period of time. In essence, such devices can be classified as either active or passive devices. The compound of the present invention may be a depot. Such depots acting for a long time can be administered, for example, by implantation subcutaneously or intramuscularly; they can also be administered by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials, such as as an emulsifier in available oils; with ion exchange resins; or as slightly soluble derivatives, such as slightly soluble salts.

  A therapeutically effective amount of a compound of the invention may be administered as a single dose, as a bolus dose, or as an intermittent dose for long-term administration. Therefore, in the case of intermittent application dose, the bolus administration of the compound of the present invention is performed, and after a period for administering the compound of the present invention to the subject, the second bolus administration is performed. In one example, the compound of the invention is administered in intermittent application doses daily, weekly or monthly, but is not limited to this example.

  In one example, a therapeutically effective amount of a compound of the present invention is combined with a therapeutically effective amount of another agent, such as an additional appetite suppressant, an agent that lowers food intake, decreases the amount of glucose in plasma, or in plasma It is administered together with drugs that change the amount of lipids. Examples of additional appetite suppressants include, but are not limited to, ampepramon (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramine, sibutramine, rimonabant and fluoxetine. The compounds of the present invention can be administered concurrently with the additional appetite suppressant, or may be administered sequentially. Thus, in one embodiment, the compounds of the present invention may be administered together with a single dose of an appetite suppressant.

In another example, a therapeutically effective amount of a compound of the present invention is administered in combination with another therapeutically effective amount of an agent used to treat a disease other than obesity, such as diabetes, and as an example of an additional therapeutic agent, GLP- 1 or analogs thereof, exenatide and pramlintide, but are not limited to these.

  The compound of the present invention may be used as needed every time an effect such as an appetite suppressing effect, a food intake lowering effect, or a calorie intake lowering effect is required, or shortly before the effect is sought, for example, May be administered 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 90 minutes or about 120 minutes, about 4 hours, about 8 hours or about 12 hours before, It is not limited to these.

  When the compound of the present invention is combined with other drugs and an effect such as an appetite suppressing effect, a food intake lowering effect, or a caloric intake lowering effect is required, or just before the effect is sought, For example, about 10 minutes, about 15 minutes, about 30 minutes, about 60 minutes, about 90 minutes or about 120 minutes, about 4 hours, about 8 hours or about 12 hours before the effect is sought It may be administered, but is not limited thereto.

Dosage A therapeutically effective amount of a compound of the invention can vary depending on the molecule utilized, the patient being treated, the severity and type of the disease, and the method and route of administration. For example, a therapeutically effective amount of a compound of the present invention can vary between about 0.01 μg / kg body weight to about 1 g / kg body weight, such as about 1 μg to about 5 mg / kg body weight, or about 5 μg to about 1 mg. / Weight is 1 kg. The compounds of the present invention may be administered to a subject at 0.5-200 pmoles (pmol) / kg body weight, or about 20 pmol / kg body weight. In one example, a compound of the invention is administered at a dosage of about 1 nmol or more, a dosage of 2 nmol or more, or a dosage of 5 nmol or more, but is not limited thereto. In the examples, the dosage of the compounds of the invention generally does not exceed 100 nmol, for example a dosage of 90 nmol or less, a dosage of 80 nmol or less, a dosage of 70 nmol or less, a dosage of 60 nmol or less, a dosage of 50 nmol or less. Dose, 40 nmol or less, 30 nmol or less, 20 nmol or less, 10 nmol or less. For example, the dose range may be any combination of the prescribed minimum tolerance and the prescribed maximum tolerance. Accordingly, the dose range of the compound of the present invention is in the range of 1-100 nmol, 1-90 nmol, 1-80 nmol, but is not limited thereto.

  In one example, the compounds of the invention are administered at about 0.5 to about 50 nmol, such as, but not limited to, about 1 to about 20 nmol, such as about 2 nmol, administered as a subcutaneous injection. One of ordinary skill in the art can readily determine the exact dosage based on the potency of the particular compound used, the subject's age, weight, sex and physiological symptoms.

  In another example, a compound of the present invention may be administered to a subject at a dosage of about 0.005 mg to about 2 mg, about once, about 2, about 3 and about 4 times a day. do not do.

  Suitable dosages of the compounds of the present invention include caloric intake, food intake or appetite equal to caloric intake, reduced food intake or appetite or increased energy consumption induced by the level of oxm found in humans. Also included is an amount that causes a decrease in energy consumption or an increase in energy consumption. Examples of dosages include, but are not limited to, an amount that produces an effect observed when the plasma level of oxm is from about 800 pM to about 1300 pM, or from about 900 pM to about 1000 pM or about 950 pM.

Appropriate dosages of the compounds of the present invention include those equivalent to oxm levels found in patients experiencing anorectic conditions such as jejunal ileal bypass (Sarson et al., Int J Obes, 1981, 5:
471-480; Holst et al., Scand J Gastroenterol, 1979, 14: 205-207).

In an experiment investigating the effects of oxyntomodulin on appetite suppression and food intake suppression in humans (Cohen et al., J. Clin. Endocrinol. Metab., 2003, 88 (10), 4696-4701). It was found that injecting oxyntomodulin for 90 minutes at 0 pmol / kg.min significantly reduced any energy intake (19.3 +/− 5.6%; P <0.01). The total amount of oxyntomodulin injected was 270 pmol / kg body weight. The oxyntomodulin-like immune response in the subject's blood was approximately 800 pmol / l during the infusion.

In an experiment investigating the effect of oxyntomodulin on human weight loss (Wynne et al., Diabetes, 2005, 54 (Aug), 2390-2395), subcutaneous injection of oxyntomodulin significantly reduced body weight. During the 28-day experiment, the body weight of the treatment group was reduced by 2.3 ± 0.4 kg compared to 0.5 ± 0.5 kg (P <0.0106) in the control group. Oxint modulin 1.8 mg (about 400 nmol) was administered three times a day 30 minutes before meals. On average, the treatment group lost a further 0.45 kg in one week. The energy intake of the treatment group was 170 ± 37 kcal (25 ± 5%) (P ± 0.0007) in the first experimental diet during the 28-day experimental period without changing the food's subjective palatability. ), The last experimental meal of the 28-day experimental period was significantly reduced to 250 ± 63 kcal (35 ± 9%) (P ± 0.0023). When oxyntomodulin was treated, the weight decreased, and the amount of adipose-derived hormone changed with a decrease in adipose tissue. The appetite suppression effect continued for 4 weeks.

  It has been found that the compounds of the present invention are more effective and / or have longer duration than the native oxyntomodulin previously used in human experiments (Cohen et al. (2003) and Wynne et al. ( 2005) Diabetes 54 (Aug), 2390-2395). The dosage required of the compounds of the invention will be somewhat less than that required for native oxyntomodulin. As described in the Examples section, the potency of the peptides referred to herein as SEQ ID NO: 25, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 19 and SEQ ID NO: 29 is , And oxint modulin are 2.5 times, 200 times, 400 times, and 1 to 4000 times, respectively, and SEQ ID NO: 25, SEQ ID NO: 15, SEQ ID NO: 16 necessary to recognize human effects. , SEQ ID NO: 19 and SEQ ID NO: 29 are therefore expected to be reduced at the same rate, eg, about 2.5 times, respectively, relative to the dose of native oxyntomodulin, It is thought to be 200 times, 400 times and 1 to 4000 times less. Because the peptide efficacy of the present invention is greater than the native oxyntomodulin peptide, it is believed that the number of administrations of the compound of the invention will also be less than that required for native oxyntomodulin.

  The present invention is illustrated by the following examples, but is not limited to these examples.

Examples Materials and Methods Animals: All animal methods were approved by British Home Office Animals (Scientific Procedures) Act 1986 (Project License No. 70/5516). Male C57BL / 6 mice and male Wistar rats are temperature-regulated (21-23 ° C.), individual cages with free access to chow (RM1 feed, SDS Ltd, Weezham, Essex, UK) and water Reared in The lighting cycle has a 14 hour light period and a 10 hour dark period, starting the light period at 07:00 ('dawn'), all lights at 07:30, and the dark period at 21:00 ('') It was completely erased at 21:30. This time zone was adjusted according to the breeding facility.

  All animals were cared for almost daily for an average of 9 days before the first experiment. To further adapt to treatment during the experimental period, each animal was injected with saline twice at least 2 days apart during the environmental acclimatization period.

  Intraperitoneal (IP) injection: Mice were injected IP using a 0.5 ml syringe and a 29 gauge needle (maximum injection volume 0.1 ml). The maximum volume that can be administered by IP injection was 0.1 ml.

  Subcutaneous (SC) injection: Rats were SC injected using a 0.5 ml syringe and 29 gauge needle (maximum injection volume 0.1 ml). The maximum volume that could be administered by SC injection was 0.1 ml.

  Experimental protocol: C57BL / 6 mice (20-35 mg) were injected with peptide as a study after 20 hours of fasting. Wistar rats were injected after a 24-hour fast. The pre-weighed amount of chow was just after injection. Residual feed was weighed at regular time intervals (1, 2, 3, 4, 6, 8, 24 and 48 hours after injection) to calculate food intake.

  Cation Metabolic Experiment Protocol: Animals were kept at 24 ° C. in a 12:12 light-dark cycle (light period 0700-1900). Saline or peptide was injected the next morning or the next morning or in the afternoon just before the beginning of the dark period. Mice were injected intraperitoneally (IP) with a maximum volume of 0.1 ml, and rats were injected intraperitoneally (IP) with 0.5 ml or subcutaneously (SC) with 0.1 ml. All mice or rats were housed and acclimatized from 1 to 2 days prior to the start of injection in a metabolic laboratory cage. Rats / mouses were individually housed in special plexiglass cages (Columbus Instruments) with free access to water. Rats / mouses can freely take the round feed (RM1 diet, SDS LTd, Witham, UK) in the side feeders installed in each cage. The side feeder was stably placed on a balance directly connected to a computer that measured the food intake (FI) of each cage. The computer was set to measure food weight either once per minute or once every 30 minutes. Cumulative FI (food intake) was automatically calculated. The amount of movement of each individually housed animal was estimated using a light beam technique with OptoM3 technology (Columbus Instruments). Counts of cumulative movement in the x-axis and z-axis directions were recorded simultaneously every 30 minutes and used to determine horizontal momentum (XAMB) and vertical momentum (ZTOT), respectively.

Peptide synthesis Peptide synthesis Peptides were prepared by solid phase sequential synthesis (SPSS) using the Fmoc N-terminal protection method. Chain construction was performed on Applied Biosystems 431, 433 or a Pioneer automated synthesizer. A solid phase resin with a suitable C-terminal amino acid or amide linker preloaded at the factory was used. The following side chain protecting groups were used: Asn (Trt), Gln (Trt), Cys (Trt), His (Trt), Asp (tBu), Glu (tBu), Ser (tBu), Thr (tBu), Tyr (tBu), Arg (Pbf), Lys (Boc), Trp (Boc). Oxazolidine dipeptide prepared in advance was used instead of each monomer where synthesis was considered difficult. All chemicals were synthetic products (obtained from various vendors including Applied Biosystems, Merck Biosciences and AGCT). Feedback monitoring was performed on all devices for optimal synthesis.

Peptide recovery After synthesis, the peptide was cleaved from the solid phase resin support and all side chains were deprotected. This was done by treatment with trifluoroacetic acid (TFA) containing 4% water and 2.5% triisopropylsilane to remove side chain protecting groups for 2 hours. The peptide-TFA solution was filtered from the resin and the peptide was precipitated with methyl tertiary butyl ether (MTBE). The peptide was centrifuged, washed with MTBE and dried under vacuum.

Peptide analysis and purification Peptides were dissolved in deionized water supplemented with acetic acid as needed. The peptide solution was centrifuged or filtered (Whatman GD / X syringe filter) to remove impurities and then analyzed and purified.

  All peptide products were analyzed by reverse phase HPLC on an Applied Biosystem BioCad instrument using an analytical Brownlee Aquapore RP300C8 or Phenomenex Synergy HydroC18 column. Purification was performed by reverse phase HPLC using a previously prepared column of the type described above. The product was eluted using an acetonitrile-water gradient (with TFA as counterion). Capillary zone electrophoresis (CZE) of the crude peptide was performed using a Hewlett Packard 3DCE apparatus. Molecular weight was determined with a Micromass MALDI-R mass spectrometer.

  The purified peptide was lyophilized in a formulation glass vial (Adelphi Vials) and sealed under vacuum.

  In the examples below, “xx” or “ex” means insertion of an amino acid at the specified position to replace the corresponding numbered residue.

Derived side chains Peptides with side chains derived from acyl or alkyl groups were prepared in a general manner.
Albumin binding Analogs bound to albumin are synthesized as described above, but generally 0.5 μmol of peptide is dissolved in 50 μl of DMSO and 450 μl of phosphate buffered saline (PBS, pH 7.4) to give 0. 25 μmol (ie half the molar amount of peptide used) was dissolved in 500 μl of PBS. The albumin solution and the peptide solution were mixed and a 2% (v / v) glutaraldehyde solution was added dropwise with stirring at 4 ° C. for 2 hours. The reaction was stopped by adding 200 μl of 10 mg / ml NaBh4 at 4 ° C. for 1 hour with stirring. The resulting solution was dialyzed for 24 hours at 4 ° C. with three changes of excess PBS (0.02%, NaN 3), and the peptide-albumin conjugate was lyophilized and stored at −20 ° C.

Solubility of derived peptide The derived polypeptide must be completely dissolved prior to administration. In order to achieve solubility, it may be necessary to dissolve the polypeptide in a small amount of dilute alkali (eg, 50 μl of 0.01 NaOH) and then dilute the dissolved peptide with saline.

Example 1: Oxm Analogs with 4-10 Amino Acids Nearly Centered with Substitution Sequences To Feed Three Oxm Analogs with Substitution of 4, 7 or 10 Residues The effect of was investigated. The three compounds have the amino acid sequence of human oxyntomodulin (SEQ ID NO :) except that various lengths (4 to 10 amino acids) are substituted as follows:
It matches the total length of 7).
oxm (xx15-18): oxm (SEQ ID NO: 7) in which residues 15-18 are replaced with the sequence Glu Glu Glu Ala (SEQ ID NO: 20)
oxm (xx15-21): oxm (SEQ ID No. 21) in which residues 15-21 are replaced by the sequence Glu Glu Glu Ala Val Arg Leu (SEQ ID NO: 21)
NO: 7)
oxm (xx15-24): oxm (SEQ ID NO: 7) in which residues 15-24 are replaced with the sequence Glu Glu Glu Ala Val Arg Leu Phe Ile Glu (SEQ ID NO: 4).

The sequence is present in the middle part of the oxm molecule and does not affect the C-terminal octapeptide. The entire sequence is
oxm (xx15-18) SEQ ID NO: 14
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala
oxm (xx15-21) SEQ ID NO: 15
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala
oxm (xx15-24) SEQ ID NO: 16
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala
It is.

  The peptide was administered by injection to a group containing 9-10 mice at a dose of 2700 nmol / kg (the effective amount of human oxm is known), and the appetite suppression effect was 'evaluated'. Another group received either oxm (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 1a to 1f, which are 0 to 1 hour, 1 to 2 hours, 2 to 4 hours, 4 to 8 hours, 8 to 24 hours and 24 to 32 hours after injection, respectively Food intake during. 2a-2c show the cumulative food intake for 2, 4 and 8 hours after injection for each group. The results show that even oxm with 4 amino acids substituted (xx15-18) has improved and prolonged food intake suppression effects compared to both saline and oxm (particularly FIGS. 1d and 8). (See 2c for food intake by time). Although not statistically significant, oxm (xx15-21) and oxm (xx15-24) tend to show more potent and longer-lasting appetite suppression effects.

Example 2: Low-volume experiment Three types of peptides of the present invention were administered by injection at a dose of 300 nmol / kg to a group containing 9-10 mice. Another group received either the same amount of exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 3a-3e, but the food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is. Figures 4a-4d show the cumulative food intake at 2, 4, 8 and 24 hours after injection for each group.

The peptides tested are
oxm (xx15-24): 10 amino acid substitutions (see SEQ ID NO: 16—Experiment 1)
oxm (xx27-33): His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala
(SEQ ID NO: 19)
Exendin 4 (SEQ ID NO: 22):
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
oxm (xx15-39):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
It is.

  As shown in Example 1, oxm (xx15 to 24) has a greater influence on feeding than oxm. From FIGS. 3a-3c, oxm (xx15-24) and oxm (xx15-39) appear to be as potent as exendin for up to 4 hours. Exendin is more effective for food intake for 4-8 hours, but the cumulative data in Figure 4c shows that oxm (xx15-24) is slightly less than exendin for 8 hours immediately after injection It can be seen that the amount is reduced. From FIGS. 3a-3d, it is believed that oxm (xx27-33) is initially as potent as exendin.

Example 3: Oxm analogs in which the amino acid sequence of the non-terminal region is replaced with a substitution sequence The effects on feeding of two types of oxm analogs in which four different residues were replaced were investigated. The three compounds match the amino acid sequence of oxyntomodulin (SEQ ID NO: 1) except that the sequence length for four is substituted as follows.
oxm (xx30-33): human oxm (SEQ ID NO: 7) in which residues 30-33 are replaced with the sequence Gly Pro Ser Ser (SEQ ID NO: 23)
oxm (xx27-33): oxm (SEQ ID No. 24) with residues 27-33 replaced with the sequence Lys Asn Gly Gly Pro Ser Ser (SEQ ID NO: 24)
NO: 7).

The sequence is present in the middle part of the oxm molecule and does not attack the C-terminal tetrapeptide. The entire sequence is
oxm (xx30-33):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 17)
oxm (xx27-33):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 19)
It is.

  The peptide was administered by injection to a group containing 9-10 mice at a dose of 2700 nmol / kg (the effective amount of human oxm is known), and the appetite suppression effect was 'evaluated'. Another group received either the same amount of oxm (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 5a-5e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Figures 6a-6d show cumulative food intake at 2, 4, 8 and 24 hours after injection for each group. The results suggest that 4 amino acid substitutions improve and prolong the food intake inhibitory effect compared to both saline and oxm, especially in oxm (xx27-33).

Example 4: D-amino-His-oxm
Groups of mice, each containing 9-10 fasted mice, were injected with one of the following compounds:
1-D-amino-His-oxm (full-length human oxm with histidine at position 1 replaced with D-histidine)
Saline (control)
Pig oxm (comparison)
Human oxm (comparison).

  The administered peptide dose was 2700 nmol / kg. The food intake measured in each group is shown in FIGS. 7a-7c, which are food intakes between 0-1 hour, 1-2 hours and 2-4 hours after injection, respectively. No obvious results were obtained after 4 hours. Figures 8a-8d show the cumulative food intake at 2, 4, 8 and 24 hours after injection for each group. From these figures, it is inferred that D-amino-His-oxm has the same degree of potency as native human oxm, and the food intake suppression effect lasts longer than that of unmodified human oxm (0 to 2 and 0 to 0). P <0.05 at 4 hours).

Example 5: Substitution of Residue 2 with Ala, with or without D-amino-His modification at Residue 1 A group containing 9-10 fasted mice, each with one of the following compounds: Injected:
Oxm in which Ser of residue 2 is replaced with Ala (“Ala2-oxm”)
Oxm D-His modified and 2-Ala substituted at residue 1 (D-His-Ala2-oxm)
Oxm modified with 1-D-His at residue 1 and not substituted with 2-Ala
oxm (comparison)
Saline (control).
The sequence of D-His-Ala 2-oxm is as follows.
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 25)
The administered peptide dose was 2700 nmol / kg. The food intake measured in each group is shown in FIGS. 9a-9c, which are food intakes between 0-1 hour, 1-2 hours and 2-4 hours after injection, respectively. Figures 10a and 10b show the cumulative food intake at 2 and 4 hours after injection for each group. As expected, oxm reduced food intake. Although D-His-oxm decreased food intake in this experiment, the results were not convincingly superior to native oxm.

  Ala2-oxm did not significantly reduce food intake compared to saline (the effect is statistically distinct from native oxm). Since Ala2 modifies the peptide more like GLP-1-, it is thought that the peptide is susceptible to cleavage by dipeptidyl peptidase IV (DPPIV). D-His-Ala2-oxm is more effective than Ala2oxm in reducing food intake, which is postulated to be due to the D-amino acid at position 1 providing DPPIV protection.

  Surprisingly, D-His-Ala2-oxm reduces food intake more effectively than native oxm, and in this example, D-His-oxm. This is probably because the Ala2 modification helps the receptor binding and activation, and the DPPIV protection hypothesis is realized by D-His.

Example 6: Oxm analogs substituted for oxm 27-39 and oxm 15-39 The effects of two oxm analogs having the following sequences on feeding were investigated:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ
(ID NO: 26)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ
(ID NO: 27)
The analog SEQ ID NO: 26 is composed of oxm 1 to 26 having a tail portion corresponding to amino acids 27 to 39 of exendin 4 (that is, amino acids 27 to 39 of SEQ ID NO: 22) at the C-terminus. SEQ ID NO: 27 is composed of oxm 1 to 14 having a tail portion corresponding to amino acids 15 to 39 of exendin 4.

  The peptide was administered by injection to a group containing 9-10 mice at a dose of 2700 nmol / kg (the effective amount of human oxm is known), and the appetite suppression effect was 'evaluated'. Another group received either the same amount of native oxm (comparative purpose) or saline (control).

  The food intake measured in each group is shown in FIGS. 11a to 11d, which are food intakes between 0 to 1 hour, 1-2 hours, 2-4 hours and 4-8 hours after injection, respectively. Figures 12a-12c show the cumulative food intake at 2 and 4 hours after injection for each group.

  The results indicate that oxm26ex (SEQ ID NO: 26) and oxm14ex (SEQ ID NO: 27) have efficacy and long-lasting effects on food intake.

  So far, exendin is thought to bind to the GLP1 receptor more strongly than GLP1 itself, largely due to the lack of residue 2 alanine binding to the N-terminus, which makes exendin resistant to DPPIV. The hypothesis is true. In this example, since the exendin moiety is on the C-terminal side, it is unexpectedly considered that another action is working. The strong activity of oxm26ex and oxm14ex is thought to be due to strong resistance to endopeptidase.

Example 7: Low Volume Test Oxm26ex (SEQ ID NO: 26) and oxm14ex (SEQ ID NO: 27) were administered by injection at a dose of 1000 nmol / kg to a group containing 9-10 mice. Another group received either the same amount of native human oxm, GLP-1 or exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 13a-13e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Figures 14a-14d show the cumulative food intake at 2, 4, 8 and 24 hours after injection for each group.

  In this example, the effect of 1000 nmol / kg oxm on feeding lacked statistical significance. Exendin-4 reduced food intake. Of course, exendin is more potent than GLP-1 at this dose. Oxm26ex and oxm14ex significantly inhibit feeding compared to both saline (control) and oxm treated groups, but the effect of oxm26ex does not last as long as exendin.

Example 8: Oxm analogs with one or more substitution sequences The effects of the following oxm analogs on feeding were investigated. The three compounds match the amino acid sequence of oxyntomodulin (SEQ ID NO: 7) except that the sequence length is substituted as follows:
oxm14ex (SEQ ID NO: 27—see Example 6)
oxm (xx15-24): Example 1 See SEQ ID NO: 16.
oxm (xx15-24) (xx27-33):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 28)
D-His1-Ala2-oxm (xx15-24) (xx27-33):
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 29)
The test peptide was administered by injection at a dose of 100 nmol / kg to a group containing 9-10 mice. Another group received either the same amount of exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 15a-15d, which are food intakes between 0-1 hour, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Figures 16a-16c show the cumulative food intake for 2, 4 and 8 hours after injection for each group. The results suggest that all test peptides are more effective than saline. Figures 15d and 15e suggest that oxm (xx15-24) (xx27-33) is more effective than oxm (xx15-24). The D-His1-Ala2-oxm (xx15-24) (xx27-33) analogues are particularly long acting. In fact, FIG. 16c suggests that the analogs have long-term effects compared to exendin 4.

Example 9: Dose study To determine the dosage, the effects of the following oxm analogues on feeding were investigated:
D-His-Ala2-oxm: Example 5 SEQ ID NO: Refer to 25 oxm (xx15 to 21): Example 1 SEQ ID NO: Refer to 15 oxm (xx15 to 24): Example 1 SEQ ID NO: Refer to 16 oxm (Xx27-33): Example 3 SEQ ID NO: See 19 D-His1-Ala2-oxm (xx15-24) (xx27-33): Example 8 See SEQ ID NO: 29.

  The test peptides were administered by injection to groups containing 9-10 mice at various doses (all nmol / kg) shown in the table below.

Another group received either oxm at a dose of 1400 nmol / kg or saline (control).

  The food intake for 1 hour after injection measured in each group is shown in FIGS. The table below summarizes the activity of each test peptide compared to oxm.

  Exendin 4, which is an appetite suppressant, has a potency of about 2000 when calculated by the same method.

Example 10: Addition of Ala-Ala extension to C-terminus of oxm The effects of the following oxm analogues on feeding were investigated. The analog is consistent with the amino acid sequence of oxyntomodulin (SEQ ID NO: 1) except that two Ala moieties are added to the C-terminus, ie, positions 38 and 39.
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala (SEQ ID NO: 30)
The test peptide was administered by injection to a group containing 9-10 mice at a dose of 1400 nmol / kg. Another group received either the same amount of human oxm full length (comparison purpose) or saline (control).

  The food intake measured in each group is shown in FIGS. 18a-18b, which are food intakes between 0-1 hour and 1-2 hours after injection, respectively. FIG. 18a shows that two Ala residues increase the rate of food intake reduction over native oxm.

Example 11: Oxm derivatives in which 10 amino acids at positions 15 to 24 were replaced with substitution sequences The effects of four types of oxm analogs each substituted with 10 residues on feeding were investigated. The four compounds are in each case consistent with SEQ ID NO: 7, except that one amino acid in the substitution sequence is substituted as follows:
(I) Replacing Ala at residue 18 with Val
Val18-oxm (xx15-24): His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO : 31)
(Ii) Replacing Leu at residue 21 with Ile
Ile21-oxm (xx15-24): His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Ile Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO : 32)
(Iii) Replacing Ile at residue 23 with Leu
Leu23-oxm (xx15-24): His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Leu Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO : 33)
The test peptide was administered by injection to a group containing 9-10 mice at a dose of 100 nmol / kg. Another group received either oxm (xx15-27) or saline (control).

The food intake measured in each group is shown in FIGS. 19a to 19e, but food intake between 0 to 1 hour, 1 to 2 hours, 2 to 4 hours, 4 to 8 hours and 8 to 24 hours after injection, respectively. It is a quantity. The results of FIGS. 19a-19e show that 18Val-oxm (15-24), 21Ile-oxm (xx15-24) and Leu23-oxm (xx15-24) mutants are as potent as oxm (xx15-24). Suggests to show. Furthermore, in the case of 18 Val-oxm (xx15-24), the onset of action is delayed compared to oxm (xx15-24), but the action is longer-lasting (see FIGS. 19a-19d, in particular FIGS. 19a and 19d). See If the onset of action is delayed, the blood concentration curve becomes smoother, so even if administered in a relatively large amount, undesired initial nausea can be avoided, and the duration of the effect after administration is prolonged, so that withdrawal is possible. Sexuality decreases. Ile19-oxm (xx15-24) analogs under similar conditions:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 34)
When tested with the analogs, the analogs show a similar or slightly better effect than oxm (xx15-24), but also slightly slower than oxm (xx15-24), which is sometimes advantageous is there.

Example 12: Additional data when 2 residues are replaced with Ala, with or without D-amino-His modification, each to a group containing 9-10 fasted mice One of the test compounds was injected.

Two oxm analogs with substitution of the first amino acid (His1) were tested. The tested compound is Des-His-oxm
D-His-oxm
Pig oxm (comparison)
Human oxm (control)
The dose of peptide administered was 2700 nmol / kg. The food intake measured in each group is shown in FIGS. 20a-20c, which are food intakes between 0, 1 and 2 and 2 to 4 hours after injection, respectively. Des-His-oxm and D-his-oxm also reduced food intake. These various compounds maintained their action longer than the native oxm.

Example 13: Oxm Derivatives Fasted groups of mice were each injected with one of the following:
oxm26ex (SEQ ID NO: 26)
D-His-oxm26ex
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ ID NO: 36)
oxm14ex (SEQ ID NO: 27)
D-His-oxm14ex
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ ID NO: 57)
The compound was administered by injection to a group containing 9-10 mice at a dose of 1000 nmol / kg. Another group received either the same amount of exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 21 a to 21 c, which are food intakes between 0 to 1 hour, 1 to 2 hours and 2 to 4 hours after injection, respectively. FIG. 21d is cumulative data, showing that D-His-oxm26ex reduced food intake more than oxm26ex, and all analogs significantly reduced food intake compared to saline (control). Show.

Example 14: Comparison of oxm and acetyl oxm A group of fasted mice was each injected with one of the following:
Oxyntomodulin acetyloxyntomodulin
CH ₃ -CO-NH-CRH-CO-Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg
Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (R is a side chain group of His).

  The compound was administered by injection to a group containing 9-10 mice at a dose of 1400 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 22a-22c, which are food intakes between 0, 1 and 1-2 hours and 2-4 hours after injection, respectively.

  The data represents the activity of both compounds. The appetite suppression effect of acetyloxyntomodulin acts more slowly than oxyntomodulin.

Example 15: Oxm Mutant Fasted groups of mice were each injected with one of the following:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 37)
Ala19-Val23-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 38)
The compound was administered by injection to a group of mice at a dose of 100 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 23a-23e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. A decrease in food intake is observed in 0-4 hours.

Example 16: oxm mutant A group of fasted mice was each injected with one of the following:
Val18-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ IS NO: 40)
D-His1-Ala2-Val18-oxm (ex15-21)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 41)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 24a-24e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 24f shows the accumulated data. A decrease in food intake is observed with val18-oxm (ex15-21) at 0-2 hours and with D-His-Ala2-Val18-oxm (ex15-21) at 0-8 hours.

Example 17: oxm mutant A group of fasted mice was each injected with one of the following:
Arg27-oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Arg Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 42)
Thr29-oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 43)
The compound was administered to the group of mice by injection at a dose of 300 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 25a-25c, which are food intakes between 0, 1 and 1-2 hours and 2-4 hours after injection, respectively. A decrease in food intake is observed with Arg27-oxm (ex27-33) from 0 to 1 hour.

Example 18: Extension of oxmC-terminus Each group of fasted mice was injected with one of the following:
oxm-Ala38
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala (SEQ ID NO: 44)
oxm-Ala38,39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 45)
oxm-Ala38-42
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Ala Ala Ala (SEQ ID NO: 46)
oxm-Lys33-Ala38
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala (SEQ ID NO: 47)
The compound was administered by injection to a group of mice at a dose of 1400 nmol / kg. Another group received either native human oxm (for comparison purposes) or saline (control).

The food intake measured in each group is shown in FIGS. 26a-26e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is a quantity. FIG. 26f shows cumulative data. From 0 to 1 hour, food intake decreased for all compounds. 38
And the Ala modification at position 39 shows stronger potency than native oxm.

Example 19: Another oxmC-terminal extension Each group of fasted mice was injected with one of the following:
oxm-Ala38,39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 48)
oxm-Ala38,39, Lys40
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 49)
oxm-Ala38,39, Tyr40
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Tyr (SEQ ID NO: 50)
The compound was administered by injection to a group of mice at a dose of 1400 nmol / kg. Another group received either native eel oxm (comparative purpose) or saline (control).

  The food intake measured in each group is shown in FIGS. 27a-27e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. The addition of Lys40 at the end and the addition of the shorter extension Tyr40 reduces the effect of oxm-Ala28, 39 on food intake.

Example 20: Effect of Ala 38, 39 on replacement oxm Fasted groups of mice were each injected with one of the following:
D-His1-Ala2-oxm (ex15-24) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 51)
D-His1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 52)
The compound was administered to the group of mice by injection at a dose of 0.5, 1 or 2 nmol / kg. Another group received saline (control). The food intake measured in each group is shown in FIGS. 28a-28e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount.

  C-terminal extension reduces initial potency but maintains the effect of the peptide.

Example 21: Additional carboxy-terminal extension Each group of fasted mice was injected with one of the following:
oxm (ex15-23) (ex27-33) -Ala38,39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 53)
oxm (ex15-23) (ex27-33) -Ala38,39-Glu40,41-Lys42
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu
Glu Lys (SEQ ID NO: 54)
oxm (ex15-23) (ex27-33) -Ala38,39-Glu40,41-Lys42-palmitoyl
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl (SEQ ID NO: 55 )
The compound was administered to the group of mice by injection at a dose of 100 or 400 nmol / kg. Another group received either exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 29a-29e, and the food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. All compounds reduced food intake during the first 8 hours.

Example 22: oxm mutant A group of fasted mice was each injected with one of the following:
oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 56)
oxm (ex27-30)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 57)
oxm (ex27-31)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Arg Asn Asn Ile Ala (SEQ ID NO: 58)
The compound was administered to the group of mice by injection at a dose of 300 nmol / kg. Another group received either exendin 4 (for comparison purposes) or saline (control).

  The food intake measured in each group is shown in FIGS. 30a-30e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 30f shows the cumulative data. All compounds reduced food intake.

Example 23: oxm mutant A group of fasted mice was each injected with one of the following:
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 59)
oxm (ex16-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 60)
oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 61)
oxm (ex28-32)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln
Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Arg Asn Asn Ile Ala (SEQ ID NO: 62)
The compound was administered to the group of mice by injection at a dose of 30 or 300 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 31a-31e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Figures 31f and 31g show cumulative data. All compounds reduced cumulative food intake at least at some time points.

Example 24: oxm mutant A group of fasted mice was each injected with one of the following:
oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 61)
oxm (ex29-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 62)
The compound was administered to the group of mice by injection at a dose of 300 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 32a-32e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. All compounds reduced food intake at least at some time points.

Example 25: oxm mutant A group of fasted mice was each injected with one of the following:
oxm (ex15-23)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 63)
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 59)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 33a-33e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 33f shows cumulative data. Both compounds reduced food intake by approximately equal amounts up to 4 hours (ie, cumulatively).

Example 26: oxm with one amino acid modification (ex15-24)
Each fasted group of mice was injected with one of the following:
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
59)
Ala19-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 64)
Val23-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 68)
The compound was administered by injection to a group of mice at a dose of 100 nmol / kg. Another group received either exendin 4 (comparison) or saline (control). Modification of Ala19 and Val23 brings the sequence closer to the unmodified oxm sequence.

  The food intake measured in each group is shown in FIGS. 34a-34c, which are food intakes between 0-1 hour, 1-2 hours and 2-4 hours after injection, respectively. FIG. 34d shows cumulative data. All compounds reduced food intake at least at some time points. A single amino acid modification reduced the effect.

Example 27: oxm with one amino acid modification (ex15-24)
Each fasted group of mice was injected with one of the following:
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 59)
Asp24-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 65)
Asp17-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Asp Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 66)
Lys20-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Lys Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 67)
The compound was administered by injection to a group of mice at a dose of 100 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 35a-35d, which are food intakes between 0-1 hour, 1-2 hours, 2-4 hours and 4-8 hours after injection, respectively. FIG. 35e shows cumulative data. All compounds reduced food intake, but oxm (ex15-24) was most effective.

Example 28: oxm with amino acid modification (ex15-24)
Each fasted group of mice was injected with one of the following:
Val23-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 146)
Ala19, Val23-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 38)
The compound was administered by injection to a group of mice at a dose of 100 nmol / kg. Another group received either native oxm (comparison) or saline (control).

  The food intake measured in each group is shown in FIGS. 36a-36e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Both compounds reduced cumulative food intake.

Example 29: oxm with amino acid modification (ex15-24)
Each fasted group of mice was injected with one of the following:
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 63)
Val18-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 68)
Gln18-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Gln Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 69)
Ile19-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 70)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 37a-37e, and the food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 37f shows cumulative data. All compounds reduced cumulative food intake.

Example 30: oxm with amino acid modification (ex27-33)
Each fasted group of mice was injected with one of the following:
Oxm
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 7)
Ala38-Ala39-oxm
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 45)
oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 56)
Arg27-oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Arg Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 147)
Thr29-oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 148)
The compound was administered to groups of mice by injection at a dose of 1400 or 300 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 38a-38c, which are food intakes between 0-1 hour, 1-2 hours and 2-4 hours after injection, respectively. FIG. 38d shows cumulative data. Exchange of one amino acid in Arg27 and Thr29 reduces the effect of oxm (ex27-33) on food intake, just as if one amino acid was replaced with oxm (ex15-24).

Example 31: oxm with amino acid modification (ex27-33)
Each fasted group of mice was injected with one of the following:
oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 56)
Asn32-oxm (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Ser Asn Asn Ile Ala (SEQ ID NO: 71)
The compound was administered to the group of mice by injection at a dose of 300 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 39a-39e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. A single amino acid substitution of Asn32 reduces the effect on food intake of oxm (ex27-33).

Example 32: oxm with amino acid modification (ex15-21)
Each fasted group of mice was injected with one of the following:
oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 15)
Gln15-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 73)
Gln16-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 74)
Val18-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 40)
Val18, Ile19-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 75)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 40a-40e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 40f shows the accumulated data. All compounds reduced cumulative food intake over 8 hours.

Example 33: oxm (ex15-21) mutant Groups of fasted mice were each injected with one of the following:
oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 15)
D-His1, Ala2-oxm (ex15-21)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 76)
D-His1, Ala2-oxm (ex15-21) -Lys33-Ala38,39
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 77)
Val18-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 40)
Val18, Ala19-oxm (ex15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ala Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 75)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 41a-41e, and the food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 41f shows cumulative data. All compounds reduced cumulative food intake. N-terminal modifications maintain biological activity.

Example 34: oxm (ex15-24) mutant Groups of fasted mice were each injected with one of the following:
oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
63)
Val18-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 68)
Gln18-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Gln Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 69)
Ile19-oxm (ex15-24)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 70)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 42a-42e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. All compounds showed bioactivity. In particular, Val18-oxm (ex15-24) and Ile19-oxm (ex15-24) decreased food intake as did oxm (ex15-24) over 4 hours.

Example 35: Multiple substitutions Fasted groups of mice were each injected with one of the following:
D-His1, Ala2-oxm (ex15-24,27-33) (shown as combi in the drawing)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 51)
D-His1, Ala2, Gln15, Gln16, Gln17, Val18, Ile19, Arg20, Ile21, Phe22, Ile23, Gln24, Lys33, Ala38, Ala39-oxm (ex15-23,27-33) (shown as xple subs in the drawing)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Gln Gln Val Ile Arg Ile Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 79)
The compound was administered to the group of mice by injection at a dose of 10 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 43a-43e, but food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Both compounds were potent and sustained reductions in food intake.

Example 36: Multiple substitutions Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 80)
D-His1, Ala2, Lys33, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 81)
The compound was administered to the group of mice by injection at a dose of 3 nmol / kg. Another group received native oxm (comparison), exendin 4 (comparison) or saline (control).

  The food intake measured in each group is shown in FIGS. 44a-44e, and the food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. Both compounds exhibit biological activity, which is more potent and persistent than native oxm.

Example 37: Multiple substitutions Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 81)
D-His1, Ala2, Gln16, Val18, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 82)
D-His1, Ala2, Gln16, Val18, Ile19, Ala38, Ala39-omx (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 83)
D-His1, Ala2, Gln16, Val18, Ile19, Leu23, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Leu Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 84)
The compound was administered to groups of mice by injection at a dose of 3 nmol / kg or 100 nmol / kg. Another group received saline (control).

  FIG. 45 shows the food intake measured in each group administered with 3 nmol / kg, and FIG. 46 shows the food intake measured in each group administered with 100 nmol / kg. Figures 45a-45e and 46b-46e are food intakes between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. All compounds reduced food intake over 8 hours.

Example 38: Multiple substitution-intermediate doses A group of fasted mice was each injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 81)
D-His1, Ala2, Gln16, Val18, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 82)
D-His1, Ala2, Gln16, Val18, Ile19, Ala38, Ala39-omx (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 83)
D-His1, Ala2, Gln16, Val18, Ile19, Leu23, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Leu Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 84)
The compound was administered to the group of mice by injection at a dose of 50 nmol / kg. Another group received saline (control) and exendin 4 (comparison).

  The food intake measured in each group is shown in FIGS. 47a-47e, and the food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 47f shows cumulative data. All compounds reduced cumulative food intake.

Example 39: Effect of Lys33 and Lys40 on oxm analogs with efficacy Each group of fasted mice was injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 85)
D-His1, Ala2, Ala38, Ala39, Lys40-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 86)
D-His1, Ala2, Lys33, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 81)
The compound was administered to the group of mice by injection at a dose of 3 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 48a-e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 48f shows cumulative data. All compounds reduce cumulative food intake, especially the presence of Lys40 is effective in prolonging activity.

Example 40: Multiple substitutions Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 86)
D-His1, Ala2, Glu3, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 87)
D-His1, Ser2, Asp3, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ser Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 88)
Ala2, Asp3, Ala38, Ala39-oxm (ex15-23,27-33)
His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 89)
Gly2, Glu3, Ala38, Ala38-oxm (ex15-23,27-33)
D-His Gly Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 149)
The compound was administered by injection to a group of mice at a dose of 7 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 49a-49f, but 0-1 hour, 1-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 8-24 hours after injection, respectively. Food intake during. FIG. 49g shows cumulative data. All compounds reduced food intake.

Example 41: Substitution of residues 1 to 3 Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 86)
Tyr1, Ala2, Glu3, Ala38, Ala39) oxm (ex15-23,27-33)
Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ
(ID NO: 91)
D-His1, Ala2, Gln3, Asn9, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asn Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 92)
D-His1, Ala2, Glu3, Glu24, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 93)
D-His1, Ala2, Glu3, Glu24, Asp35, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asp Ile Ala Ala Ala (SEQ ID NO: 94)
The compound was administered by injection to a group of mice at a dose of 7 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 50a-50f, but 0-1 hour, 1-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 8-24 hours after injection, respectively. Food intake during. FIG. 50g shows cumulative data. All compounds reduced food intake.

Example 42: Further residue 1-3 substitutions Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 86)
D-His1, Ala2, Glu3, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 87)
D-His1, Ala2, Glu3, Glu24, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 93)
D-His1, Ser2, Asp3, Ala38, Ala39-oxm (ex15-23,27-33)
D-His Ser Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala (SEQ ID NO: 88)
The compound was administered to the group of mice by injection at a dose of 5 nmol / kg. Another group received either exendin 4 (comparison) or saline (control).

  The food intake measured in each group is shown in FIGS. 51a-51f, but 0-1 hour, 1-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 8-24 hours after injection, respectively. Food intake during. Figures 51g and 51h show cumulative data. All compounds reduced food intake and in some cases this activity was more sustained than exendin-4.

Example 43: Dose Response
Each fasted group of mice was injected with one of the following:
oxm
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 7)
D-His-Ala2-oxm
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 95)
The compound was administered to the group of mice by injection at various doses (described in nmol / kg in FIG. 52). Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 52a-52d, which are food intakes between 0-1 hour, 1-2 hours, 2-4 hours and 4-8 hours after injection, respectively.

  D-His-Ala1-Oxm was more effective than oxm. The minimum effective dose of D-His-Ala2-Oxm was about 250 nmol / kg, which reduced food intake by 84.3% during the first hour. D-His-Ala2-Oxm reduces food intake at higher doses of 1400 nmol / kg as does native oxm.

Example 44: Addition of side chains Fasted groups of mice were each injected with one of the following:
Lys30-hexadecanoate-oxm (shown as Lys30 in the drawing)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys-hexadecanoate Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 97)
Lys33-hexadecanoate-oxm (shown as Lys33 in the drawing)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-hexadecanoate Asn Asn Ile Ala (SEQ ID NO: 98)
The compound was administered to the group of mice by injection at various doses (described in nmol / kg in FIG. 53). Another group received oxm (comparison) or saline (control).

  The food intake measured in each group is shown in FIGS. 53a-53e, and the food intake during 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 53f shows cumulative data. Side chain addition did not clearly reduce the bioactivity of the compound.

Example 45: Palmitoyl side chain Fasted groups of mice were each injected with one of the following:
Lys33-palmitoyl-oxm (shown as palm33 in the drawing)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 99)
The compound was administered to the group of mice by injection at various doses (described in nmol / kg in FIG. 54). Another group received oxm (comparison) or saline (control).

  The food intake measured in each group is shown in FIGS. 54a-54e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 53f shows cumulative data. Side chain addition prolonged the activity of the analogue for a period of 1-2 hours.

Example 46: Palmitoyl side chain Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Lys33-palmitoyl-oxm (ex15-21) (shown as combipalm33 in the drawing)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 100)
Lys33-palmitoyl-oxm (shown as palm33 in the drawing)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 99)
The compound was administered to the group of mice by injection at various doses (described in nmol / kg in FIG. 55). Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 55a-55e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 53f shows cumulative data.

  Side chain addition did not clearly reduce the bioactivity of the compound. The side chain addition prolonged the reduction in food intake for a period of 4-8 hours.

Example 47: Palmitoyl side chain Fasted groups of mice were each injected with one of the following:
Lys33-palmitoyl-oxm (shown as palm33 in the drawing)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 99)
D-His, Ala2-oxm (ex15-21) Lys33-palmitoyl (shown as combipalm33 in the drawing)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 100)
D-His, Ala2, Val18-oxm (ex15-21) Lys33-palmitoyl (shown as Val18combipalm33 in the drawing)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 101)
The compound was administered to groups of mice by injection at various doses (described in nmol / kg in FIG. 56). Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 56a-56d, which are food intakes between 0-1 hour, 1-2 hours, 2-4 hours and 4-8 hours after injection, respectively. FIG. 56e shows cumulative data. All compounds reduced food intake at least at some time points. Figures 57a and 57f are the results of similar but separate experiments using the same peptide at different doses. Figures 57a-57e are food intakes between 0-1 hours, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. FIG. 57f shows the accumulated data.

Example 48: Lauroyl side chain on Lys40 Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 85)
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 105 )
Lauroyl derivatives are added to 50 μl of 0.01 M NaOH with an additional 0.1 M NaOH.
Easily dissolve in 50 μl added to a final volume of 1.56 ml (using saline).

  The compound was administered to the group of mice by injection at various doses (described in nmol / kg in FIG. 58). Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 58a-58e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. All compounds reduced food intake.

Example 49: Palmitoyl side chain on Lys33 or Lys40 Fasted groups of mice were each injected with one of the following:
oxm-Lys33-palmitoyl
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 99)
D-His1Ala2, Lys33-palmitoyl-oxm (ex15-21)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala (SEQ ID NO: 100)
D-His1, Ala2, Lys33-palmitoyl, Ala38,39-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys-palmitoyl Asn Asn Ile Ala Ala Ala (SEQ ID NO: 103)
D-His1, Ala2, Lys33, Ala38,39, Lys40-palmitoyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-palmitoyl (SEQ ID NO: 104 )
The compound was administered to groups of mice by injection at various doses (described in nmol / kg in FIG. 59). Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 59a-59e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 59f shows cumulative data. All compounds reduced cumulative food intake. Palmitoyl derivatives show sustained activity.

Example 50: Comparison of palmitoyl side chain and lauroyl side chain Fasted groups of mice were each injected with one of the following:
D-His1, Ala2, Lys33-palmitoyl, Ala38,39-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys-palmitoyl Asn Asn Ile Ala Ala Ala (SEQ ID NO: 103)
D-His1, Ala2, Ala38,39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 105 )
D-His1, Ala2, Ala38,39, Lys40-palmitoyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-palmitoyl (SEQ ID NO: 106 )
The compound was administered by injection to a group of mice at 100 nmol / kg. Another group received saline (control).

  The food intake measured in each group is shown in FIGS. 60a-60e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. FIG. 60f shows cumulative data. All compounds reduced cumulative food intake. The Lys40 derivative is more potent than the Lys33 derivative. Palmitoyl derivatives are more potent at the initial time point and lauroyl derivatives are more potent over a period of 4-8 hours.

Example 51: Complex mutants A group of fasted mice was each injected with one of the following:
Ala38, Ala39, Glu40, Glu41, Lys42-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 107)
Ala38, Ala39, Lys40, Lys41, Lys42-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys Lys Lys (SEQ ID NO: 108)
Ala38, Ala39, Lys40, Lys41, Lys42-palmitoyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys Lys Lys-palmitoyl (SEQ ID NO: 109 )
D-His1, Ala2, Ala38, Ala39, Glu40, Glu41, Lys42-palmitoyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Ar
g Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl (SEQ ID NO: 110)
Compounds were administered to groups of mice by injection at 100 nmol / kg or 400 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 61a-61e, and the food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. Amount. All compounds reduced food intake.
Example 52: Compound mutants tested at different doses Fasted groups of mice were each injected with one of the following:
Ala38, Ala39, Glu40, Glu41, Lys42-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 107)
Ala38, Ala39, Glu40, Glu41, Lys42-lauroyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-lauroyl (SEQ ID NO: 111 )
Ala38, Ala39, Glu40, Glu41, Lys42-palmitoyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl (SEQ ID NO: 112 )
The compound was administered to groups of mice by injection at 20 or 50 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 62a-62e, but food between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is intake. All compounds reduced food intake.
Example 53: Compound mutants tested at different doses A group of fasted mice was each injected with one of the following:
Ala38, Ala39, Glu40, Glu41, Lys42-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 107)
Ala38, Ala39, Glu40, Glu41, Lys42-lauroyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-lauroyl (SEQ ID NO: 111 )
Ala38, Ala39, Glu40, Glu41, Lys42-palmitoyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl (SEQ ID NO: 112 )
The compound was administered to groups of mice by injection at 5 or 10 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 63a to 63h, which are 0 to 1 hour, 1 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 hours after injection, respectively. Food intake between hours, 10-12 hours and 12-24 hours. FIG. 63 i is cumulative data of food intake. All compounds reduced food intake.
Example 54: Comparison of acyl side chains Each group of fasted mice was injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 85)
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 104 )
D-His1, Ala2, Ala38, Ala39, Lys40-palmitoyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-palmitoyl (SEQ ID NO: 106 )
D-His1, Ala2, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 105 )
Ala38, Ala39, Glu40,41, Lys42-lauroyl-oxm (ex15-23) (ex27-33)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-lauroyl (SEQ ID NO: 111 )
The compound was administered to the group of mice by injection at 10 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 64a to 64g, which are 0 to 1 hour, 1 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 10 after injection, respectively. Food intake between hours and 10-24 hours. FIG. 64h shows cumulative data. All compounds (except for D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-21) (ex27-33) already proven to have reduced food intake) .
Example 55: Comparison of acyl side chains Each group of fasted mice was injected with one of the following:
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys (SEQ ID NO: 85)
D-His1, Ala2, Lys33, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 104 )
D-His1, Ala2, Ala38, Ala39, Lys40-lauroyl-oxm (ex15-23) (ex27-33)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-lauroyl (SEQ ID NO: 105 )
Compounds were administered by injection to groups of mice at 3, 7 or 10 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 65a-65e, with food between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is intake. FIG. 65f shows cumulative data. All compounds reduced food intake.
Example 56: Comparison of acyl and PEG side chains Fasted groups of mice were each injected with one of the following:
D-His1, Ala2-oxm (ex15-23) (ex27-33) -Lys33, Ala38, Ala39, Glu40, Glu41-Lys42
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 113 )
D-His1, Ala2, Asp3, Gln16, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 114 )
D-His1, Ala2, Asp3, Gln16, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42-Octanoyl
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys-Octanoyl (SEQ ID NO : 115)
D-His1, Ala2, Asp3, Gln16, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42-PEG
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys-PEG (SEQ ID NO : 116)
Compounds were administered by injection to groups of mice at 6 or 20 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 66a to 66g, but 0 to 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 6 hours, and 6 to 8 after injection, respectively. Food intake between time and 8-24 hours. FIG. 66h shows cumulative data. All compounds reduced cumulative food intake compared to saline (control).
Example 57: Comparison of acyl side chains Each group of fasted mice was injected with one of the following:
D-His1, Ser2, Asp3-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42
D-His Ser Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 117 )
D-His1, Ser2, Asp3, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42D-His Ser Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys (SEQ ID NO: 118)
D-His1, Ser2, Asp3, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42-Lauroyl
D-His Ser Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys-Lauroyl (SEQ ID NO : 119)
D-His1, Ser2, Asp3-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42-Lauroyl
D-Ser Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Glu Glu Lys-Lauroyl (SEQ ID NO : 120)
Compounds were administered by injection to groups of mice at 6 or 20 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 67a to 67g, which are 0 to 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 6 hours, 6 to 8 after injection, respectively. Food intake between time and 8-24 hours. FIG. 67h shows cumulative data. All compounds reduced food intake at several time points. In particular, D-His1, Ser2, Asp3, Val18-oxm (ex15-23) (ex27-33) Lys33, Ala38, Ala39, Glu40, Glu41, Lys42-lauroyl analogues compared to saline (control), Cumulative food intake was significantly reduced.
Example 58
Each fasted group of mice was injected with one of the following:
D-His1, Ala2-oxm
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 25)
D-His1, Val2-oxm
D-His Val Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 121)
The compound was administered to the group of mice by injection at 1400 nmol / kg. Another group received saline and human oxm as negative and positive controls, respectively.

The food intake measured in each group is shown in FIGS. 68a-68d, which are 0-1 hour, 1-2 hours, 2-4 hours, 3-4 hours, 4-8 hours and 8-24 after injection, respectively. The food intake during the time. FIG. 68e shows cumulative data. Both compounds reduced food intake at several time points.
Example 59
Each of the fasted groups of mice was injected with:
D-Ala37-oxm
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile D-Ala (SEQ ID NO: 122)
The compound was administered by injection to a group of mice at 2700 nmol / kg. Another group received saline and human oxm as negative and positive controls, respectively.

The food intake measured in each group is shown in FIGS. 69a-69b, which are food intakes between 0-1 hour and 0-2 hours after injection, respectively. D-Ala37-oxm reduced food intake compared to saline (control).
Example 60
Each of the fasted groups of mice was injected with:
oxm (xx15-39) = “ox14ex”:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Glu Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ
(ID NO: 123)
Glu20-oxm (xx27-39) = “ox26ex”:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Glu Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ
(ID NO: 124)
The compound was administered to the group of mice by injection at a dose of 2700 nmol / kg. Another group received either the same amount of human oxm (for comparison purposes) or saline (control). Both compounds reduced food intake at several time points compared to both saline and human oxyntomodulin experiments.

The food intake measured in each group is shown in FIGS. 70a-70e, but food intake between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is a quantity.
Example 61
Each of the fasted groups of mice was injected with:
Oxm (xx15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 15)
D-His1, Ala2-oxm (xx15-21)
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 76)
D-His1, Ala2-oxm (15-21) -Lys33, Ala38, Ala39
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala Ala (SEQ ID NO: 77)
Val18-oxm (xx15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 40)
Val18, Ala19-oxm (xx15-21)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ala Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 75)
The compound was administered to the group of mice by injection at a dose of 30 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 71a-71e, with food between 0-1 hour, 1-2 hours, 2-4 hours, 4-8 hours and 8-24 hours after injection, respectively. It is intake. FIG. 71f shows cumulative data. All compounds reduced food intake at several time points compared to saline (control).
Example 62
Each of the fasted groups of mice was injected with:
1/4 Exendin-4 (SEQ ID NO: 22)
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/82 DHis1-Ala2-Glu3-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 87)
24/203 DHis1-Ala2-Glu3-oxm (ex15-23) -Glu24- (ex27-33) -Ala38,39 (SEQ ID NO: 93)
24/84 DHis1-Ser2-Asp3oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 88)
The compound was administered to the group of mice by injection at a dose of 5 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIGS. 72a-72f, which are 0-1 hour, 1-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 8-24 after injection, respectively. The food intake during the time. FIG. 72g shows cumulative data. All compounds reduced food intake at several time points compared to saline (control). The peptides of the present invention showed an advantageous effect compared to exendin 4, which was more potent during the first hour but soon disappeared.
Example 63
Each of the fasted groups of mice was injected with:
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/44 DHis1-Ala2-oxm (ex15-23) -Arg27- (ex27-33) -Ala38,39 (SEQ ID NO: 125)
24/41 DHis1-Ala2-Gln17-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 120)
The compound was administered to the group of mice by injection at a dose of 6 nmol / kg. Another group received saline (control).

The food intake measured in each group is shown in FIG. All compounds reduced food intake at several time points compared to saline (control).
Example 64
Each of the fasted groups of mice was injected with:
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/42 DHis1-Ala2-Ser18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 127)
24/43 DHis1-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 128)
The compound was administered to the group of mice by injection at a dose of 6 nmol / kg (predicted from the description in FIG. 74). Another group received saline (control).

The food intake measured in each group is shown in FIG. All compounds reduced food intake at several time points compared to saline (control).
Example 65
Each of the fasted groups of mice was injected with:
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/43 DHis1-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 128)
24/82 DHis1-Ala2-Glu3-oxm (ex15-23) (ex27-33) -Ala, 38,39 (SEQ ID NO: 87)
24/84 DHis1-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Ala, 38, 39 (SEQ ID NO: 88)
The compound was administered to the group of mice by injection at the dosage shown in FIG. Another group received saline (control).

The food intake measured in each group is shown in FIG. At several time points, both compounds were found to have reduced food intake compared to saline (control). The replacement of Leu18 has a favorable effect on the profile and is a preferred feature of certain embodiments.
Example 66
A group of fasted mice was injected with:
24/110 DHis-Ser2-Glu3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 110)
23/102 DHis1-Ser2-Glu3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (SEQ ID NO: 129)
The compound was administered to the group of mice by injection at the dose shown in FIG. Another group received saline (control).

The food intake measured in each group is shown in FIG. Further data
DHis1-Ser2-Glu3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl
The dose response is also shown.
Example 67
A group of fasted mice was injected with:
1/4: Exendin 4 (3 nmol / kg) (SEQ ID NO: 22)
24/76: DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 113)
23/77: His1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (SE
(Q ID NO: 132)
23/79: DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Palmitoyl (SEQ ID NO: 110)
The compound was administered to the group of mice by injection at the dose shown in FIG. Another group received saline (control).

The food intake measured in each group is shown in FIG. Acylation alters the response profile observed so far.
Example 68
A group of fasted mice was injected with:
23/77 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Glu40,41-Lys42-Lauroyl (SEQ ID NO: 132)
23/79 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Glu40,41-Lys42-Palmitoyl (SEQ ID
NO: 110)
The compound was administered to the group of mice by injection at the dosage shown in FIG. Another group received saline (control).

The food intake measured in each group is shown in FIG. Modification with lauroyl and palmitoyl did not prove any obvious difference between the two.
Example 69
A group of fasted mice was injected with:
24/76 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (3 nmol / kg)
(SEQ ID NO: 113)
24/102 DHis1-Ser2-Glu3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (1 and 3 nmol / kg) (SEQ ID NO: 133)
23/102 DHis1-Ser2-Glu3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (3 nmol / kg) (SEQ ID NO: 129)
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (3 nmol / kg) (SEQ ID NO: 86) (Comparison)
24/44 DHis1-Ala2-oxm (ex15-23) -Arg27- (ex27-33) -Ala38,39 (3 nmol / kg) (SEQ ID NO: 125)
Another group received saline (control). The food intake measured in each group is shown in FIG.
Example 70
For fasted mice:
24/76 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO:
113)
24/102 Backbone (skeleton) similar to 24/76 but DHis1-Ser2-Glu3 (SEQ
(ID NO: 133)
24/104 Same backbone as 24/7 but DHis1-Ser2-Asp3 (SEQ ID NO: 117)
24/110 Same as 24/102 (DHis1-Ser2-Glu3) but with Val18 added (SEQ ID NO: 134)
23/104 Backbone similar to 24/104 (DHis1-Ser2-Asp3), but lauroyl is added to Lys42 (SEQ ID NO: 120)
Was injected.

The compound was administered at the dosage shown in FIG. Another group received saline (control). The food intake measured in each group is shown in FIG.
Example 71
A group of fasted mice was injected with:
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/43 DHis1-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 128)
24/82 DHis1-Ala2-Glu3-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 87)
24/84 DHis1-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 88)
The compound was administered at the dosage shown in FIG. Another group received saline (control). The food intake measured in each group is shown in FIG.
Example 72
For fasted mice:
24/104 DHis1-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (6 nmol / kg) (SEQ ID NO: 117)
24/112 Backbone similar to 24/104 but with Val18 (6 nmol / kg) (SEQ ID NO: 118)
23/112 24/112 (6 and 20 nmol / kg) with lauroyl side chain in Lys42 (SEQ ID NO: 119)
23/104 Lys42-Lauroyl 24/104 (20 nmol / kg) (SEQ ID NO: 120)
Was injected.

Another group received saline (control). The food intake measured in each group is shown in FIG.
Example 73
A group of fasted mice was injected with:
24/104 DHis1-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 117)
24/210 DHis1-Ala2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 114)
24/114 DHis1-Ser2-Asp3-Gln16, Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 135)
Another group received saline (control). All compounds were administered at a dose of 6 nmol / kg. The food intake measured in each group is shown in FIG.
Example 74
A group of fasted mice was injected with:
15/1 DHis1-Ala2-oxm (ex15-24) (ex27-33) (SEQ ID NO: 51)
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/29 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40 (SEQ ID NO: 85)
24/75 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40,41-Lys42 (SEQ ID NO: 137)
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40-Lauroyl (SEQ ID NO: 105)
23/75 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40,41-Lys42-Palmitoyl (SEQ ID
NO: 131)
Another group received saline (control). Compounds were injected at the dosages shown in FIG. The food intake measured in each group is shown in FIG.
Example 75
A group of fasted mice was injected with:
25/1 Met, Asn, Glu, Asp, Lys, Arg-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 138)
25/2 Met, Asn, Glu, Asp, Lys, Arg-DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 139)
Another group received saline (control). Compounds were injected at the dosages shown in FIG. The food intake measured in each group is shown in FIG. 85 (other data not mentioned in this example is also present in FIG. 85).
Example 76
A group of fasted mice was injected with:
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40-Lauroyl (SEQ ID NO: 105)
28/75 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40,41-Lys42-Mouse albumin (albumin-conjugate ratio was 20: 1) (SEQ ID NO: 140)
Another group received saline (control).

Compounds were injected at the dosages shown in FIG. The food intake measured in each group is shown in FIG.
Example 77
A group of fasted mice was injected with:
24/76 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO:
113)
24/210 DHis1-Ala2-Asp3-Gln16, Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO: 114)
23/210 DHis1-Ala2-Asp3-Gln16, Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Octanoyl (SEQ ID NO: 115)
27/210 DHis1-Ala2-Asp3-Gln16, Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-PEG (albumin-conjugate ratio was 20: 1) (SEQ (ID NO: 116)
Another group received saline (control). Compounds were injected at the dosages listed in FIG. The food intake measured in each group is shown in FIG.
Example 78
A group of fasted mice was injected with:
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40-Lauroyl (SEQ ID NO: 105)
28/76 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40,41-Lys42-Mouse Albumin (SEQ ID NO: 140) (Albumin binding ratio was 2: 1)
Another group received saline (control).

Compounds were injected at the dosages shown in FIG. The food intake measured in each group is shown in FIG.
Example 79
A group of fasted mice was injected with:
Saline
exendin-4 (SEQ ID NO: 22)
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) Ala38,39-Lys40-Lauroyl. (SEQ ID NO: 105)
Injections were made once a day for the first 7 days, twice a day until the 10th day.

  Compounds were injected at the dosages shown in FIG. FIG. 89a shows the change in body weight from baseline body weight of mice injected once a day during the 1st to 7th day of the experiment (in the dark).

  FIG. 89b shows the change in body weight from baseline body weight of mice injected twice daily during the 1-7 day period of the experiment (in the dark period).

  FIG. 89c shows the change in body weight from baseline body weight for mice injected twice daily during the 7-10 day period of the experiment (in the dark period).

  FIG. 89d shows 24-hour food intake during the 1-7 day period of the experiment.

  FIG. 89e shows the 24-hour food intake during the 7-10 day period of the experiment.

FIG. 89f shows food intake for 2 hours after the afternoon injection in the 1-10 day period of the experiment.
Example 80
To a group of fasted rats:
Saline
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40-Lauroyl (SEQ ID NO: 105)
Was injected.

The dose is shown in FIG. Subcutaneous injections were made once a day in the afternoon for the first 3 days, and food intake was examined over 72 hours. The data is shown in FIG.
Example 81
To a group of fasted large rats (maximum body weight = 420 g):
Saline
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40-Lauroyl (SEQ ID NO: 105)
Were injected intraperitoneally or subcutaneously.

The dose was 10 nmol / kg. The data is shown in FIG.
Example 82
To a group of fasted rats:
Saline
23/104 DHis2-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (intraperitoneal injection 10 nmol / kg) (SEQ ID NO: 120)
23/104 DHis2-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (subcutaneous injection 5, 10 30 nmol / kg) (SEQ ID NO: 120)
Was injected.

Data regarding food intake is shown in FIG. It can be seen that peptides delivered by intraperitoneal injection behave better than those delivered by the subcutaneous route.
Example 83
To the group of fasted rats:
Saline
23/104 DHis2-Ser2-Asp3-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42-Lauroyl (SEQ ID NO: 120)
Was injected.

The dose and route of administration (intraperitoneal injection or subcutaneous injection) were as shown in FIG. Data on food intake is shown in FIG. It can be seen that the peptide showed biological activity when transported by either route.
Example 84
To a group of fasted rats:
Saline
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40Lauroyl (SEQ ID NO: 105)
Was injected.

The dose and route of administration (intraperitoneal injection or subcutaneous injection) were as shown in FIG. The data regarding food intake is shown in FIG. It can be seen that the peptide showed biological activity when transported by either route.
Example 85
To a group of fasted rats:
Saline
24/40 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 86)
24/43 DHis1-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 128)
Was injected.

The dose and route of administration (intraperitoneal injection or subcutaneous injection) were as shown in FIG. Data on food intake is shown in FIG. It can be seen that the peptide showed biological activity when transported by either route.
Example 86
To a group of fasted rats:
Saline
24/29 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40 (SEQ ID NO: 85)
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40Lauroyl (SEQ ID NO: 105)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 87
To a group of fasted rats:
Saline
24/78 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42 (SEQ ID NO:
113)
23/79 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42Palmitoyl (SEQ ID NO: 110)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 88
To a group of fasted rats:
Saline
23/36 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Ala38,39-Lys40Lauroyl (SEQ ID NO: 105)
23/79 DHis1-Ala2-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42Palmitoyl (SEQ ID NO: 110)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 89
To a group of fasted rats:
Saline
24/43 DHis-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SQE ID NO: 128)
24/314 DHis1-Ser2-Asp3-Ala18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 141)
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 142)
24/318 DHis1-Ser2-Asp3-Ile18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 143)
24/322 DHis1-Ser2-Asp3-Val18-Ala19-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO:
144)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 90
To a group of fasted rats:
Saline
24/43 DHis-Ala2-Leu18-oxm (ex15-23) (ex27-33) -Ala38,39 (SEQ ID NO: 128)
24/300 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33 (SEQ ID NO: 150)
24/301 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Asn34,35-Stop (SEQ ID NO: 151)
24/302 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Asn34,35-Lys36-Stop (SEQ ID NO: 152)
24/303 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Ala38,39-Glu40,41-Lys42
(SEQ ID NO: 153)
Was injected.

The dose was as shown in FIG. Data regarding food intake is shown in FIG.
Example 91
To a group of fasted rats:
Saline
24/300 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33 (SEQ ID NO: 150)
24/314 DHis1-Ser2-Asp3-Ala18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 141)
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 142)
24/320 DHis1-Ser2-Asp3-Gln16-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO:
154)
24/324 DHis1-Ser2-Asp3-Ala16-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO:
155)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG. The data corroborates previous observations that peptides with Leu18 show a suitable and preferred activity profile and are therefore preferred peptides.
Example 92
To a group of fasted rats:
Saline
24/318 DHis1-Ser2-Asp3-Ile18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 143)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG. The data shows a dose response profile of the injected compound.
Example 93
To a group of fasted rats:
Saline
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 142)
24/330 DHis1-Ala2-Glu3-Leu18-oxm (ex15-24) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 156)
24/331 DHis1-Ala2-Asp3-Leu18-oxm (ex15-24) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 157)
24/337 DHis1-Ala2-Asp3-Leu18-oxm (ex15-24) (ex27-33) -Lys33-Asp35-Lys38 (SEQ ID NO:
158)
24/327 DHis1-Ala2-Asp3-Ile18-Lys20-Tyr21-oxm (ex15-23) (ex27-33) -Lys33- Lys38 (SEQ
(ID NO: 159)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 94
To a group of fasted rats:
Saline
24/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 114)
23/310 DHis1- Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38-Octanoyl (SEQ ID
NO: 160)
23/311 DHis1- Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38-Lauroyl (SEQ ID NO: 161)
23/312 DHis1- Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38-Palmitoyl (SEQ I
D NO: 162)
27/310 DHis1- Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38-PEG (SEQ ID NO: 163)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 95
To a group of fasted rats:
Saline
24/327 DHis1-Ser2-Asp3-Ile18-Lys20, Tyr21-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 164)
24/330 DHis1-Ala2-Glu3-Leu18-oxm (ex15-24) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 156)
24/331 DHis1-Ala2-Asp3-Leu18-oxm (ex15-24) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 157)
24/310 DHis1-Ala2-Asp3-Val18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 114)
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 142)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 96
To a group of fasted rats:
Saline
24/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 114)
23/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-octanoyl (SEQ ID NO: 160)
23/311 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-lauroyl (SEQ ID NO: 161)
23/312 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-palmitoyl (SEQ ID NO: 162)
27/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-PEG (SEQ ID NO: 163)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 97
To a group of fasted rats:
Saline
24/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 114)
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 142)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 98
To a group of fasted rats:
Saline
24/314 DHis1-Ser2-Asp3-Ala18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 141)
24/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 114)
24/316 DHis1-Ser2-Asp3-Leu18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 142)
24/318 DHis1-Ser2-Asp3-Ile18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 143)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 99
To a group of fasted rats:
Saline
24/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 114)
23/310 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-octanoyl (SEQ ID NO: 160)
23/311 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-lauroyl (SEQ ID NO: 161)
23/312 DHis1-Ser2-Asp3-Val18-oxm (ex15-23) (ex27-33) Lys33-Lys38-palmitoyl (SEQ ID NO: 162)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 100
To a group of fasted rats:
Saline
1/4 Exendin-4 (SQE ID NO: 22)
24/310 D-His1-Ser2-Asp3-Val18-OXM (ex15-23) (ex27-33) -Lys 33-Lys 38 (SEQ ID NO: 114)
23/310 D-His1-Ser2-Asp3-Val18-OXM (ex15-23) (ex27-33) -Lys 33-Lys 38-octanoyl (SQE ID NO: 160)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 101
To a group of fasted rats:
Saline
1/4 Exendin-4 (SEQ ID NO: 165)
240/10 D-His1-Leu18-Exendin-4 (SEQ ID NO: 165)
24/340 D-His1-Ser2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Ala37-NH2 (SEQ ID NO: 166)
24/342 D-His1-Ala2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Ala37-NH2 (SEQ ID NO: 167)
24/344 D-His1-Ala2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Lys38-NH2 (SEQ ID NO: 168)
Was injected.

The dose was as shown in FIG. Data on food intake is shown in FIG.
Example 102
To a group of fasted mice:
Saline
1/4 Exendin-4 (SEQ ID NO: 22)
24/342 D-His1-Ala2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Ala37-NH2 (SEQ ID NO: 167)
24/344 D-His1-Ala2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Lys38-NH2 (SEQ ID NO: 168)
23/344 D-His1-Ala2-Gln16, Leu18-OXM (ex15-23) (ex27-33) Lys38-Lauroyl (SEQ ID NO: 169)
Was injected.

The dose is shown in FIG. Data on food intake is shown in FIG.
Example 103
To a group of fasted mice:
Saline
24/344 D-His1-Ala2-Gln3-Gln16, Leu18-OXM (ex15-23) (ex27-33) Lys38-NH2 (SEQ ID NO: 168)
24/331 D-His1-Ala2-Asp3, Leu18-OXM (ex15-24) (ex27-33) Lys33-Lys38 (SEQ ID NO: 157) 23/344 D-His1-Ala2-Gln3-Gln16, Leu18-OXM (ex15-23) (ex27-33) Lys38-Lauroyl (SEQ ID NO: 169)
Was injected.

The dose is shown in FIG. Data on food intake is shown in FIG.
Example 104
To a group of fasted mice:
Saline
24/343 D-His1-Ala2-Asp3-Ile18-OXM (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 170) 24/347 D-His1-Ala2-Asp3-Gln16-Ile18- Lys20-Tyr21-OXM (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 171)
24/348 D-His1-Ala2-Asp3-Ile18-Lys20-Tyr21-Val23-OXM (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 172)
24/349 D-His1-Ala2-Asp3-Arg15-Ile16-Ile18-Lys20-Tyr21-OXM (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 173)
24/350 D-His1-Ala2-Asp3-Lys15-Ile16-Ile18-Lys20-Tyr21-OXM (ex15-23) (ex27-33) -Lys33-Lys38 (SEQ ID NO: 174)
Was injected.

The dose is shown in FIG. Data regarding food intake is shown in FIG.
Example 105
To a group of fasted mice:
Saline
24/331 D-His1-Ala2-Asp3-Leu18-OXM (ex15-24) (ex27-33) Lys33-Lys38 (SEQ ID NO: 157)
24/370 D-His1-Ala2-Asp3-Leu18-OXM (ex15-23) (ex27-33) Lys33-Lys38 (SEQ ID NO: 175)
23/370 D-His1-Ala2-Asp3-Leu18-OXM (ex15-23) (ex27-33) Lys33-Lys38-Octanoyl (SEQ ID NO: 176)
23/371 D-His1-Ala2-Asp3-Leu18-OXM (ex15-23) (ex27-33) Lys33-Lys38-Lauroyl (SEQ ID NO: 177)
23/372 D-His1-Ala2-Asp3-Leu18-OXM (ex15-23) (ex27-33) Lys33-Lys38-Palmitoyl (SEQ ID
NO: 178)
Was injected.

The dose is shown in FIG. Data on food intake is shown in FIG.
Example 106
To a group of fasted mice:
Saline
1/4 Exendin-4 (SEQ ID NO: 22)
24/331 D-His1-Ala2-Asp3, Leu18-OXM (ex15-24) (ex27-33) Lys33-Lys38 (SEQ ID NO: 157) was injected.

The dose is shown in FIG. Data regarding food intake is shown in FIG.
Other Exemplary Sequences Other sequence examples included within the scope of the present invention are shown below using single letter amino acid abbreviations. It will be understood that the present invention encompasses not only the sequences shown below, but also variants and derivatives thereof as described herein. In the sequences shown below, it should be noted that the amino acid abbreviation “H” at the beginning of the sequence means “D-histidine”.
HADGTFTSDYSKYLRIELVKYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFVGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFIGWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFVEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFIEWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFVGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFIGWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFVEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFVGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFIGWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFVEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFIEWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIVRVRVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFVGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIVRVRVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFIGWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFVEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFIEWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFIEWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVKYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFVQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRYFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVKLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEIELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLREELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLEEELVRLFIQWLKNGGPSKNNIA
HADGTFTSDYSKYLRIELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVKYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLRIELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFVQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRYFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVKLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEIELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLREELVRLFIQWLMNTKRNKNNIA
HADGTFTSDYSKYLEEELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVKYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFVQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRYFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVKLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEIELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLREELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLEEELVRLFIQWLKNGGPSKNNIA
HAEGTFTSDYSKYLRIELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVKYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVKLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLRIELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFVQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRYFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVKLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEIELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLREELVRLFIQWLMNTKRNKNNIA
HAEGTFTSDYSKYLEEELVRLFIQWLMNTKRNKNNIA

FIGS. 1a, 1b, 1c, 1d, 1e and 1f show the post-injection experimental results comparing the appetite-suppressing effect of the three compounds of the present invention on mice with native human oxyntomodulin and saline. It is a figure shown according to this time interval. Figures 2a, 2b and 2c are diagrams showing cumulative food intake over time. FIGS. 3a, 3b, 3c, 3d and 3e are graphs showing the experimental results comparing the appetite-suppressing effect of the three compounds of the present invention with exendin 4 and saline depending on the specific time interval after injection. 4a, 4b, 4c and 4d are diagrams showing the cumulative food intake over time calculated from the data shown in FIGS. Figures 5a, 5b, 5c, 5d and 5e show the effect of the two compounds of the present invention on the appetite suppressive effect on mice in the same time interval after injection comparing the same amount of human oxm and saline. FIG. 6a, 6b, 6c and 6d are diagrams showing cumulative food intake over time calculated from the data shown in FIGS. Figures 7a, 7b and 7c show the results of an experiment comparing the appetite-suppressing effect of a single compound of the present invention on mice with human oxm, porcine oxm and saline depending on the specific time interval after injection. It is. Figures 8a, 8b, 8c and 8d show cumulative food intake over time for the compounds described in Figures 7a-7c. FIGS. 9a, 9b and 9c are graphs showing the experimental results comparing the appetite suppression effect produced by the three compounds of the present invention with human oxm and saline depending on the specific time interval after injection. 10a and 10b are diagrams showing cumulative food intake over time calculated from the data shown in FIGS. 9a to 9c. FIGS. 11a, 11b, 11c and 11d are graphs showing experimental results comparing the appetite suppression effect brought about by the two compounds of the present invention with human oxm and saline according to specific time intervals after injection. 12a, 12b and 12c are diagrams showing cumulative food intake calculated from the data shown in FIGS. 11a to 11d. Figures 13a, 13b, 13c, 13d and 13e show experimental results comparing the appetite-suppressing effect of the two compounds of the invention shown in Figures 11a-11d in lower amounts with human oxm, exendin 4 and saline. It is a figure shown according to the specific time interval after injection. 14a, 14b, 14c, and 14d are diagrams showing the cumulative food intake over time calculated from the data shown in FIGS. 13a to 13e. FIGS. 15a, 15b, 15c and 15d are graphs showing the experimental results comparing the appetite-suppressing effect brought about by the four compounds of the present invention with exendin 4 and saline according to specific time intervals after injection. 16a, 16b and 16c are diagrams showing the cumulative food intake over time calculated from the data shown in FIGS. 15a to 15d. FIGS. 17a, 17b, 17c, 17d and 17e show experimental results comparing the appetite suppression effect obtained when five compounds of the present invention are administered to mice at various doses compared to human oxm and saline. It is. FIGS. 18a and 18b are graphs showing experimental results comparing the appetite-suppressing effect of one compound of the present invention with human oxm and saline depending on the specific time interval after injection. FIGS. 19a to 19e are graphs showing experimental results compared with saline (control) by monitoring the appetite suppression effect brought about by the four compounds of the present invention at specific time intervals after injection. It is a figure which shows the further experimental result which monitored the appetite suppression effect which the compound of this invention brings about at the specific time interval after injection, and compared with the salt solution (control).

Claims (96)

Formula (I):
Z-X-S1 (I)
Represented by
X is oxm 4-14;
Z is an amino acid sequence having 3 amino acid residues;
S1 is an amino acid sequence corresponding to row A (SEQ ID NO: 1), or m amino acids of said row A correspond to m corresponding to residues 15 to 37 of row B (SEQ ID NO: 2) An amino acid corresponding to row A, wherein t amino acid residues in row A are substituted with corresponding t amino acid residues in residues 15 to 24 in row R The row A, the row B and the row R (SEQ ID NO: 145) are as follows:

The compound optionally further has an extension linked to an amino acid at position 37, the optional extension comprising one or more amino acids,
m is an integer of 1 or more,
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, provided that when S1 matches the row A, Z is not His Ser Gln, the general formula (I ), A mutant or derivative thereof, or a salt or solvate thereof.   The compound according to claim 1, wherein t = 0.   2. A compound according to claim 1, wherein t = 5 or more.   The compound according to any one of claims 1, 2 and 3, wherein Z is an amino acid sequence consisting of two amino acid residues following Gln, Asp or Glu.   5. A compound according to any one of claims 1 to 4, wherein the amino acid substitution according to row B comprises at least one sequence group consisting of at least 3 amino acids.   6. A compound according to any one of claims 1 to 5, characterized in that the substituted amino acid comprises a sequence group consisting of at most 12 amino acids. The following groups:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ
(ID NO: 26)
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser;
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Ile Arg Glu Glu Ile Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
The compound according to any one of claims 1 to 6, which is represented by a sequence formula selected from: The compound is represented by the general formula (II):
Z-X-S2-Y (II)
Represented by
X and Z are as defined in claim 1 or claim 4;
Y is oxm 25-37;
S2 is the amino acid sequence corresponding to row C (SEQ ID NO: 3), where n amino acids in row C are replaced with n corresponding amino acids from row D (SEQ ID NO: 4) And the u amino acids in row C are replaced with u corresponding amino acids from row S (SEQ ID NO: 145), wherein row C, row D and row S are: And

n is an integer of 1 or more,
u is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, a compound represented by the general formula (II), a mutant or derivative thereof, or a salt or Solvate.   The compound according to claim 8, wherein u = 0.   9. A compound according to claim 8, wherein u = 5 or more.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution according to row D comprises at least 3 amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution by row D comprises at least one sequence group consisting of 2 or more amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution according to row D comprises a sequence group consisting of at least 4 amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution according to row D comprises a sequence group consisting of at most 10 amino acids.   The compound according to claim 13 or 14, wherein the sequence group has 5 to 10 amino acids.   The compound according to any one of claims 13 to 15, wherein the sequence group has 6 to 10 amino acids.   The compound according to any one of claims 13 to 16, wherein the sequence group has 7 to 10 amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution by row S comprises at least 3 amino acids.   11. A compound according to any one of claims 8, 9 or 10, characterized in that the amino acid substitution by row S comprises at least one sequence group consisting of 2 or more amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution by row S comprises a sequence group consisting of at least 4 amino acids.   11. A compound according to any one of claims 8, 9 or 10, wherein the amino acid substitution by row S comprises a sequence group consisting of at most 10 amino acids.   The compound according to claim 20 or 21, wherein the sequence group has 5 to 10 amino acids.   The compound according to any one of claims 20 to 22, wherein the sequence group has 6 to 10 amino acids.   The compound according to any one of claims 20 to 23, wherein the sequence group has 7 to 10 amino acids. Array
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 14),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 15),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 16).
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Ile Arg Glu Glu Leu Val Lys Tyr Phe Val Gly Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Ile Arg Ile Glu Leu Val Lys Leu Phe Val Gly Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Lys Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Asp Ala Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Gln Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Lys Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Ile Arg Ile Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Asn Ile Ala Ala Ala
The compound according to claim 8, wherein the compound is The compound has the general formula (III):
ZX'-S3-Y '(III)
Represented by
X ′ is oxm 4 to 26;
Z is as defined in claim 1 or 4;
Y ′ is oxm 34-37;
S3 is an amino acid sequence corresponding to row E (SEQ ID NO: 5), but the p amino acids in row E are replaced with p corresponding amino acids from row F (SEQ ID NO: 6) The row E and the row F are as follows:

p is an integer greater than or equal to 1, The compound of the claim | item 1, its variant, or a derivative | guide_body, its salt, or a solvate.   27. The compound of claim 26, wherein the substituted amino acid comprises at least 3 amino acids.   28. A compound according to claim 26 or 27, wherein the substituted amino acid comprises at least one sequence group consisting of two or more amino acids.   29. The compound of claim 28, wherein the substituted amino acid comprises a sequence group consisting of at least 3 amino acids.   30. A compound according to any one of claims 26 to 29, characterized in that the substituted amino acid comprises a sequence group consisting of at most 7 amino acids.   31. The compound according to claim 30, wherein the sequence group has 3 to 7 amino acids.   32. The compound of claim 31, wherein the sequence group has 4 amino acids.   31. The compound according to any one of claims 28 to 30, wherein the sequence group has 4 to 7 amino acids. Array
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 17),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 18),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala (SEQ ID NO: 19),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Ser Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln
Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Arg Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Thr Gly Pro Ser Ser Asn Asn Ile Ala
The compound according to claim 26, wherein the compound is Formula (IV):
ZX-S2-Trp-Leu-S3-Y '(IV)
In the formula,
Z and X are as defined in claim 1 or claim 4;
S2 is as defined in any one of claims 8 to 24;
S3 and Y 'are as defined in any one of claims 26 to 33, the compound represented by the sequence formula (IV), The following groups:
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Gln Glu Val Ile Arg Leu Phe Leu Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Gln Gln Gln Val Ile Arg Ile Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys,
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ile Val Arg Tyr Phe Val Gly Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys, D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala; D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Arg Glu Glu Ile Val Lys Leu Phe Ile Gly Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala
36. The compound according to claim 35, wherein the compound has a sequence selected from: Formula (V):
Z-X-S4-S5-E (V)
In the formula,
X is oxm 4-14;
Z is as defined in claim 1 or claim 4;
S4 is the sequence Glu Glu Glu Ala Val Arg Leu Phe Ile Glu (SEQ ID NO: 35) containing the sequence of Asp Ser Arg Arg Ala Gln Asp Phe Val Gln (SEQ ID NO: 35). 0 to 1 optionally in the corresponding position of the sequence Arg Ile Glu Ile Val Lys Tyr Phe Val Gly (SEQ ID NO: 145), comprising 1 to 10 amino acids present in the corresponding position of ID NO: 4) 10 amino acids containing 9 amino acids and 0-5 amino acids not identical to the amino acids present in the corresponding positions of SEQ ID NO: 4, SEQ ID NO: 145 and SEQ ID NO: 35 Represents an array consisting of;
S5 represents oxm25-37 or at positions 27-33 at least one residue is the sequence Lys (27) Asn (28) Gly (29) Gly (30) Pro (31) Ser (32) Ser (33 ) Represents oxm 25-37 substituted with one or more residues numbered correspondingly (SEQ ID NO: 24);
E represents any extension having one or more amino acid residues, a compound represented by the general formula (V), a variant or derivative thereof, or a salt or solvate thereof.   38. The compound of claim 37, wherein S4 comprises at least 3 amino acids present in the corresponding position of either SEQ ID NO: 4 or SEQ ID NO: 145.   38. The compound of claim 37, wherein S4 comprises at least one amino acid different from the amino acid present at the corresponding position of SEQ ID NO: 4, SEQ ID NO: 145 and SEQ ID NO: 35. .   S4 is at least 6 amino acids present in the corresponding position of SEQ ID NO: 4 or SEQ ID NO: 145, and in the corresponding position of SEQ ID NO: 4, SEQ ID NO: 145 or SEQ ID NO: 35 38. The compound of claim 37, comprising at least one amino acid different from the existing amino acid.   S4 is present in the corresponding positions of SEQ ID NO: 4 or SEQ ID NO: 145, and the corresponding positions of SEQ ID NO: 4, SEQ ID NO: 145 and SEQ ID NO: 35 38. The compound according to claim 37, comprising at least one amino acid different from the amino acid to be formed. S5 represents -Trp-Leu-S3-Y ',
44. Any one of claims 37 to 41, wherein Y 'is as defined in claim 26 and S3 is as defined in any one of claims 26 to 33. The compound according to item. The compound has the following sequence:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 31),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Ile Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO:
32),
His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Ile Glu Leu Val Arg Tyr Phe Val Glu Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Lys
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Leu Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 33),
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Ile Arg Leu Phe Ile Glu Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala (SEQ ID NO: 34);
D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Leu Val Lys Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala
D-His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser
43. The compound of claim 42, wherein the compound has one of:   44. The compound according to any one of claims 1 to 43, wherein Z represents His-Ser-Gln. Z represents the ABC section, where
A is an amino acid other than L-histidine,
B is L-alanine or L-serine;
45. The compound according to any one of claims 1 to 44, wherein C is L-aspartate, L-glutamate or L-glutamine.   Z is D-His-Ala-Gln; D-His-Ala-Glu; D-His-Ala-Asp; D-His-Ser-Gln; D-His-Ser-Glu; or D-His-Ser- 46. A compound according to claim 45, characterized in that it represents Asp. X is as defined in claim 1;
S1 in any case corresponds to the sequence of row A as defined in claim 1 and has at least 6 amino acids;
And Z is A ¹ -A ² -A ^3- ;
A ¹ is an amino acid other than L-histidine;
A ² is Ala or Ser;
A ³ is, Gln, A compound according to claim 1, characterized in that the Glu or Asp. A compound according to claim 47, wherein A ¹ is a D- amino acid.   49. The compound of claim 48, wherein the D-amino acid is D-histidine. A ¹ is D- histidine, is A ² is L- alanine The compound of claim 47, wherein A ³ is L- glutamate or L- aspartate.   51. A compound according to any one of claims 47 to 50, wherein S1 comprises all of said row A. The compound according to any one of claims 1 to 51, wherein the terminal residue is an amide group.   52. A compound according to any one of claims 1 to 51, having an extension consisting of at least two amino acids. Extensions shown below:
Ala (38) -Ala (39), -Lys (38), -Ala (38) -Ala (39) -Lys (40), -Ala (38) -Ala (39) -Lys (40) -Lys ( 41), -Ala (38) -Ala (39) -Glu (40) -Glu (41) -Lys (42)
54. The compound of claim 53, having one of:   54. The compound of claim 53, having an extension -Pro (38) -Ser (39).   A compound having the formula: oxm-Ala (38) Ala (39).   57. The compound according to any one of claims 1 to 56, wherein at least one of the amino acid residues has an alkyl side chain or an acyl side chain.   58. The compound of claim 57, wherein the one or more alkyl side chains or the acyl side chains are selected from the group consisting of hexadecyl, dodecyl, palmitoyl and lauroyl.   59. A compound according to claim 57 or 58 having an acyl side chain attached to an amino acid residue at one or more of positions 30, 33, 38, 40 and 42. The following groups:
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-lauroyl Asn Asn Ile Ala,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala, D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala, D-His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Leu Val Lys Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Lys-palmitoyl
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Val Val-palmitoyl Arg Leu Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala, D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-palmitoyl,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-palmitoyl,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Val Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys Asn Asn Ile Ala Ala Ala Lys-lauroyl,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Ly
s-palmitoyl,
D-His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Arg Ile Glu Leu Val Arg Tyr Phe Val Glu Trp Leu Lys Asn Gly Gly Pro Ser Lys-lauroyl Asn Asn Ile Ala
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Lys-lauroyl,
D-His Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Lys-palmitoyl Asn Asn Ile Ala Ala Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Gln Trp Leu Lys Asn Gly Gly Pro Ser Ser Asn Asn Ile Ala Ala Ala Glu Glu Lys-palmitoyl.
58. The compound of claim 57 having a sequence formula selected from:   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another amino acid present at positions 4 to 37 is substituted with another amino acid. The compound according to any one of claims 1 to 60.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, two additional amino acids present at positions 4 to 37 are substituted with another amino acid. 62. The compound according to any one of claims 1 to 61.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, further three amino acids existing at positions 4 to 37 are substituted with another amino acid. 63. A compound according to any one of claims 1 to 62.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, further four amino acids existing at positions 4 to 37 are substituted with another amino acid. The compound according to any one of claims 1 to 63.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 5 amino acids existing at positions 4 to 37 are substituted with another amino acid. The compound according to any one of claims 1 to 64.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 6 amino acids existing at positions 4 to 37 are substituted with another amino acid. The compound according to any one of claims 1 to 65.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 7 amino acids present at positions 4 to 37 are substituted with another amino acid. The compound according to any one of claims 1 to 66.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 8 amino acids existing at positions 4 to 37 are substituted with another amino acid. 68. The compound according to any one of claims 1 to 67.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 9 amino acids existing at positions 4 to 37 are substituted with another amino acid. 69. The compound according to any one of claims 1 to 68.   In addition to the sequence substitution defined in the rows A, B, C, D, E, F, R and S, another 10 or more amino acids present at positions 4 to 37 are substituted with another amino acid. 70. A compound according to any one of claims 1 to 69.   71. Mutant compound according to any one of claims 61 to 70, wherein the mutant compound retains at least some activity of the corresponding non-mutant compound.   62. The mutant compound exhibits stronger appetite suppressant activity, better efficacy, a therapeutically more useful profile, or a slower clearance rate compared to the corresponding non-mutant compound. 70. The mutant compound according to any one of up to 70. At least one of the additional amino acid substitutions described above is in the following table:

The variant compound according to any one of claims 61 to 70, which is a conservative amino acid substitution described in the above.   74. A variant compound according to claim 73, wherein all of said further amino acid substitutions are conservative amino acid substitutions listed in the table shown in claim 66. Formula (VI):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala-X (VI)
Where, where
A compound, variant or derivative thereof, or a salt or solvate thereof, characterized in that X is an amine group or at least one amino acid.   76. The compound of claim 75, wherein X is 1 amino acid.   76. The compound of claim 75, wherein X is 2 amino acids.   76. The compound of claim 75, wherein X is 3 amino acids.   76. The compound of claim 75, wherein X is 4 amino acids.   76. The compound of claim 75, wherein X is 5 amino acids. X is Ala-Y,
76. The compound of claim 75, wherein Y is optionally one or more amino acids or absent. The following groups:
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Lys, His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Ala Ala Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Arg Asn Asn Ile Ala Ala Ala Tyr, His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys-dodecyl Arg Asn Arg Asn Asn Ile Ala,
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-dodecyl Asn Asn Ile Ala;
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys-palmitoyl Asn Asn Ile Ala
84. The compound according to any one of claims 75 to 81, wherein the compound has a sequence selected from: Formula (VII):
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr lys Arg Asn Arg Asn Asn Ile Ala (VII)
Or a compound represented by the general formulas (I) to (V), wherein the amino acid residue 30 is Lys,
i) acyl or PEG is derived from Lys (30); or And the compound represented by the general formula (VII), wherein an acyl side chain or a PEG side chain is derived from the Lys.   84. A pharmaceutical product comprising the compound of any one of claims 1 to 83 and one or more pharmaceutically acceptable carriers. 90. Treatment of obesity or diabetes or other complications associated with obesity in said subject in need of treatment and prevention, characterized in that the compound according to any one of claims 1 to 83 is administered to the subject. Method or preventive method.   84. A method for reducing food intake of the subject, for reducing appetite of the subject, comprising administering to the subject the compound according to any one of claims 1 to 83. A method for reducing a subject's caloric intake, for reducing the subject's body weight, for suppressing an increase in the subject's weight, or for increasing the subject's energy consumption.   87. The method of claim 85 or 86, wherein the subject is fat.   87. The method of claim 85 or 86, wherein the subject is obese.   87. The method of claim 85 or 86, wherein the subject is diabetic.   90. The method according to any one of claims 85 to 89, wherein the compound is administered peripherally.   90. Any one of claims 85-89, wherein the compound is administered subcutaneously, intravenously, intramuscularly, intranasally, transdermally, transmucosally, orally or sublingually. The method described in 1.   84. Use of a compound according to any one of claims 1 to 83 for the manufacture of a medicament for the treatment of obesity or diabetes.   Reduce the subject's appetite, reduce the subject's food intake, reduce the subject's caloric intake, reduce the subject's weight, suppress the subject's weight gain, or the subject's energy 84. Use of a compound according to any one of claims 1 to 83 for the manufacture of a medicament for increasing consumption.   The compound according to any one of claims 1 to 83, which is used as a medicine.   84. Compound according to any one of claims 1 to 83, characterized in that it is used as a drug for the treatment or prevention of obesity or diabetes or other complications associated with obesity.   Reduce the subject's appetite, reduce the subject's food intake, reduce the subject's caloric intake, reduce the subject's weight, suppress the subject's weight gain, or the subject's energy The compound according to any one of claims 1 to 83, which is used as a drug for increasing consumption.

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